Skip to content
2000
image of FDA-Approved Fluorine-Containing Molecules in 2024: Significance, Synthesis, and Therapeutic Applications

Abstract

For the past 75 years, the development pipeline of fluorinated drugs has exemplified the strategic use of fluorine to enhance key pharmacological properties, including bioavailability, metabolic stability, and target affinity. Consequently, fluorine incorporation has become a cornerstone in drug design, inspiring continuous research and development efforts across both academic and industrial sectors. Each year, numerous reviews highlight the ongoing importance of fluorinated drugs and aim to keep the field updated on emerging advancements. This review provides a comprehensive evaluation of the structural and functional benefits of fluorine in medicinal chemistry, presenting an extensive analysis of FDA-approved fluorine-containing drugs from 2015 to 2024. Special attention is paid to the latest approvals from 2024, with a focus on their mechanisms of action and detailed synthetic methodologies.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/ctmc/10.2174/0115680266388061250917093142
2025-09-23
2025-12-16

  • From This Site

    /content/journals/ctmc/10.2174/0115680266388061250917093142
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Ali S. Bolinger A.A. Zhou J. Highlights on fluorine-containing drugs approved by U.S. FDA in 2023. Curr. Top. Med. Chem. 2024 24 10 843 849 10.2174/0115680266300245240223070242 38445700
    [Google Scholar]
  2. Niu Z.X. Hu J. Sun J.F. Wang Y.T. Fluorine in the pharmaceutical industry: Synthetic approaches and application of clinically approved fluorine-enriched anti-infectious medications. Eur. J. Med. Chem. 2024 271 116446 10.1016/j.ejmech.2024.116446 38678824
    [Google Scholar]
  3. Henary E. Casa S. Dost T.L. Sloop J.C. Henary M. The role of small molecules containing fluorine atoms in medicine and imaging applications. Pharmaceuticals 2024 17 3 281 10.3390/ph17030281 38543068
    [Google Scholar]
  4. Gillis E.P. Eastman K.J. Hill M.D. Donnelly D.J. Meanwell N.A. Applications of fluorine in medicinal chemistry. J. Med. Chem. 2015 58 21 8315 8359 10.1021/acs.jmedchem.5b00258 26200936
    [Google Scholar]
  5. Shah P. Westwell A.D. The role of fluorine in medicinal chemistry. J. Enzyme Inhib. Med. Chem. 2007 22 5 527 540 10.1080/14756360701425014 18035820
    [Google Scholar]
  6. Mei H. Han J. Fustero S. Medio-Simon M. Sedgwick D.M. Santi C. Ruzziconi R. Soloshonok V.A. Fluorine‐containing drugs approved by the FDA in 2018. Chemistry 2019 25 51 11797 11819 10.1002/chem.201901840 31099931
    [Google Scholar]
  7. Howard J.A.K. Hoy V.J. O’Hagan D. Smith G.T. How good is fluorine as a hydrogen bond acceptor? Tetrahedron 1996 52 38 12613 12622 10.1016/0040‑4020(96)00749‑1
    [Google Scholar]
  8. Meanwell N.A. Fluorine and fluorinated motifs in the design and application of bioisosteres for drug design. J. Med. Chem. 2018 61 14 5822 5880 10.1021/acs.jmedchem.7b01788 29400967
    [Google Scholar]
  9. Richardson P. Applications of fluorine to the construction of bioisosteric elements for the purposes of novel drug discovery. Expert Opin. Drug Discov. 2021 16 11 1261 1286 10.1080/17460441.2021.1933427 34074189
    [Google Scholar]
  10. Ruiz-Cabello J. Barnett B.P. Bottomley P.A. Bulte J.W.M. Fluorine ( 19 F) MRS and MRI in biomedicine. NMR Biomed. 2011 24 2 114 129 10.1002/nbm.1570 20842758
    [Google Scholar]
  11. van Heeswijk R.B. Bauer W.R. Bönner F. Janjic J.M. Mulder W.J.M. Schreiber L.M. Schwitter J. Flögel U. Cardiovascular molecular imaging with fluorine-19 MRI: The road to the clinic. Circ. Cardiovasc. Imaging 2023 16 9 e014742 10.1161/CIRCIMAGING.123.014742 37725674
    [Google Scholar]
  12. Starke L. Millward J.M. Prinz C. Sherazi F. Waiczies H. Lippert C. Nazaré M. Paul F. Niendorf T. Waiczies S. First in vivo fluorine-19 magnetic resonance imaging of the multiple sclerosis drug siponimod. Theranostics 2023 13 4 1217 1234 10.7150/thno.77041 36923535
    [Google Scholar]
  13. O’Hagan D. Perry R. Lock J.M. Meyer J.J.M. Dasaradhi L. Hamilton J.T.G. Harper D.B. High levels of monofluoroacetate in Dichapetalum braunii. Phytochemistry 1993 33 5 1043 1045 10.1016/0031‑9422(93)85020‑R
    [Google Scholar]
  14. Klingensmith C.W. A note on the natural occurrence of fluoroacetic acid, the acid of the new rodenticide “1080”. Science 1945 102 2659 622 623 10.1126/science.102.2659.622
    [Google Scholar]
  15. Giesecke A.H. First use of halothane in the United States, C. Ronald Stephen, M.D. (1916-2006). Bull. Anesth. Hist. 2008 26 2 1 4 10.1016/S1522‑8649(08)50011‑4 20506766
    [Google Scholar]
  16. Inoue M. Sumii Y. Shibata N. Contribution of organofluorine compounds to pharmaceuticals. ACS Omega 2020 5 19 10633 10640 10.1021/acsomega.0c00830 32455181
    [Google Scholar]
  17. Wang J. Sánchez-Roselló M. Aceña J.L. del Pozo C. Sorochinsky A.E. Fustero S. Soloshonok V.A. Liu H. Fluorine in pharmaceutical industry: Fluorine-containing drugs introduced to the market in the last decade (2001-2011). Chem. Rev. 2014 114 4 2432 2506 10.1021/cr4002879 24299176
    [Google Scholar]
  18. Wong D.T. Perry K.W. Bymaster F.P. Case history: The discovery of fluoxetine hydrochloride (Prozac). Nat. Rev. Drug Discov. 2005 4 9 764 774 10.1038/nrd1821 16121130
    [Google Scholar]
  19. Hillhouse T.M. Porter J.H. A brief history of the development of antidepressant drugs: From monoamines to glutamate. Exp. Clin. Psychopharmacol. 2015 23 1 1 21 10.1037/a0038550 25643025
    [Google Scholar]
  20. Becnel Boyd L. Maynard M.J. Morgan-Linnell S.K. Horton L.B. Sucgang R. Hamill R.J. Jimenez J.R. Versalovic J. Steffen D. Zechiedrich L. Relationships among ciprofloxacin, gatifloxacin, levofloxacin, and norfloxacin MICs for fluoroquinolone-resistant Escherichia coli clinical isolates. Antimicrob. Agents Chemother. 2009 53 1 229 234 10.1128/AAC.00722‑08 18838594
    [Google Scholar]
  21. Zhou Y. Wang J. Gu Z. Wang S. Zhu W. Aceña J.L. Soloshonok V.A. Izawa K. Liu H. Next generation of fluorine-containing pharmaceuticals, compounds currently in phase II–III clinical trials of major pharmaceutical companies: New structural trends and therapeutic areas. Chem. Rev. 2016 116 2 422 518 10.1021/acs.chemrev.5b00392 26756377
    [Google Scholar]
  22. a Sheikhi N. Bahraminejad M. Saeedi M. Mirfazli S.S. A review: FDA-approved fluorine-containing small molecules from 2015 to 2022. Eur. J. Med. Chem. 2023 260 115758 10.1016/j.ejmech.2023.115758 37657268
    [Google Scholar]
  23. b Purser S. Moore P.R. Swallow S. Gouverneur V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 2008 37 2 320 330 10.1039/B610213C 18197348
    [Google Scholar]
  24. Hagmann W.K. The many roles for fluorine in medicinal chemistry. J. Med. Chem. 2008 51 15 4359 4369 10.1021/jm800219f 18570365
    [Google Scholar]
  25. You F. Li C. Zhang S. Zhang Q. Hu Z. Wang Y. Zhang T. Meng Q. Yu R. Gao S. Sitagliptin inhibits the survival, stemness and autophagy of glioma cells, and enhances temozolomide cytotoxicity. Biomed. Pharmacother. 2023 162 114555 10.1016/j.biopha.2023.114555 36966667
    [Google Scholar]
  26. Brodsky R.A. Paroxysmal nocturnal hemoglobinuria. Blood 2014 124 18 2804 2811 10.1182/blood‑2014‑02‑522128 25237200
    [Google Scholar]
  27. Griffin M. Hillmen P. Munir T. Richards S. Arnold L. Riley K. Hill A. Significant hemolysis is not required for thrombosis in paroxysmal nocturnal hemoglobinuria. Haematologica 2019 104 3 e94 e96 10.3324/haematol.2018.198846 30287620
    [Google Scholar]
  28. Hillmen P. Young N.S. Schubert J. Brodsky R.A. Socié G. Muus P. Röth A. Szer J. Elebute M.O. Nakamura R. Browne P. Risitano A.M. Hill A. Schrezenmeier H. Fu C.L. Maciejewski J. Rollins S.A. Mojcik C.F. Rother R.P. Luzzatto L. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med. 2006 355 12 1233 1243 10.1056/NEJMoa061648 16990386
    [Google Scholar]
  29. Danicopan. 2025 Available from: https://www.pmda.go.jp/PmdaSearch/iyakuDetail/GeneralList/39990E6
  30. First oral treatment against residual haemolytic anaemia in patients with paroxysmal nocturnal haemoglobinuria. 2024 Available from: https://www.ema.europa.eu/en/news/first-oral-treatment-against-residual-haemolytic-anaemia-patients-paroxysmal-nocturnal-haemoglobinuria
  31. Drug trials snapshots: VOYDEYA. 2024 Available from: https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-voydeya
  32. Lee J.W. Griffin M. Kim J.S. Lee Lee L.W. Piatek C. Nishimura J. Carrillo Infante C. Jain D. Liu P. Filippov G. Sicre de Fontbrune F. Risitano A. Kulasekararaj A.G. Barcellini W. Barraco F. Beneitez Pastor D. Capra M. Chew L.P. Chrysavgi L. De Castro C. de la Tour R.P. De Oliveira M.M. Di Bona E. Forcade E. Fu C-L. Furha C. Gaya Valls A. Giannouli S. Gonzalez-Fernandez A. Griffin M. Gural A. Gutierrez E.O. Hernández-Rodríguez I. Ibrahim I. Iori A.P. Ishida T. Jang J.H. Kim J-A. Kim J.S. Kitano T. Kosugi H. Kreiniz N. Kulasekararaj A. Lee J.W. Lee Lee L.W. Mayer J. Mitchell L. Mori Y. Nishiwaki K. Notaro R. Nunez R. Obara N. Oliva E.N. Patriquin C. Pessoa V. Piatek C. Piekarska A. Raza S. Risitano A.M. Rojnuckarin P. Samuel D. Shammo J. Tadmor T. Takami A. Tamari R. Terriou L. Uchiyama H. Vannucchi A.M. Yamaguchi H. Addition of danicopan to ravulizumab or eculizumab in patients with paroxysmal nocturnal haemoglobinuria and clinically significant extravascular haemolysis (ALPHA): A double-blind, randomised, phase 3 trial. Lancet Haematol. 2023 10 12 e955 e965 10.1016/S2352‑3026(23)00315‑0 38030318
    [Google Scholar]
  33. Danicopan as add-on therapy to a C5 inhibitor in paroxysmal nocturnal hemoglobinuria (PNH) participants who have clinically evident extravascular hemolysis (EVH)(ALPHA). Patent NCT04469465 2025
  34. Muvaffak E. Mokresh M.E. Varda A. Lakmoush M. Ilter M.K. Safety and efficacy of danicopan in patients with paroxysmal nocturnal hemoglobinuria: A systematic review and meta-analysis. Expert Rev. Hematol. 2024 17 11 819 831 10.1080/17474086.2024.2422558 39453029
    [Google Scholar]
  35. Kang C. Danicopan: First approval. Drugs 2024 84 5 613 618 10.1007/s40265‑024‑02023‑6 38528310
    [Google Scholar]
  36. Venkat G.R. Qiup W.I. Godwin P. Akihiro H. Dawei C. Xiangzhu W. Atul A. Milind D. Jason W.A. Avinash P. Aryl, heteroaryl, and heterocyclic compounds for treatment of complement mediated disorders. Patent WO2015130838 2015
  37. Avinash P. Morphic forms of complement factor D inhibitors. Patent WO2020051538A1 2020
  38. Phadke A.P. Hashimoto A. Andres M. Preparation of stable crystalline forms of complement factor d inhibitors for therapeutic use. Patent WO2020069024A1 2020
  39. Kilburn L.B. Khuong-Quang D.A. Hansford J.R. Landi D. van der Lugt J. Leary S.E.S. Driever P.H. Bailey S. Perreault S. McCowage G. Waanders A.J. Ziegler D.S. Witt O. Baxter P.A. Kang H.J. Hassall T.E. Han J.W. Hargrave D. Franson A.T. Yalon Oren M. Toledano H. Larouche V. Kline C. Abdelbaki M.S. Jabado N. Gottardo N.G. Gerber N.U. Whipple N.S. Segal D. Chi S.N. Oren L. Tan E.E.K. Mueller S. Cornelio I. McLeod L. Zhao X. Walter A. Da Costa D. Manley P. Blackman S.C. Packer R.J. Nysom K. The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: The phase 2 FIREFLY-1 trial. Nat. Med. 2024 30 1 207 217 10.1038/s41591‑023‑02668‑y 37978284
    [Google Scholar]
  40. FDA grants accelerated approval to tovorafenib for patients with relapsed or refractory BRAF-altered pediatric low-grade glioma. 2024 Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tovorafenib-patients-relapsed-or-refractory-braf-altered-pediatric
  41. Tovorafenib approved for some children with low-grade glioma. 2024 Available from: https://www.cancer.gov/news-events/cancer-currents-blog/2024/pediatric-low-grade-glioma-tovorafenib-braf
  42. Juric D. Kalinsky K. Turner N.C. Jhaveri K.L. Schmid P. Loi S. Saura C. First-line inavolisib/placebo + palbociclib + fulvestrant (Inavo/Pbo+Palbo+Fulv) in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer who relapsed during/within 12 months of adjuvant endocrine therapy completion: INAVO120 phase III randomized trial additional analyses. J. Clin. Oncol. 2024 42 1003 1003 10.1200/JCO.2024.42.16_suppl.1003
    [Google Scholar]
  43. A study to evaluate tovorafenib in pediatric and young adult participants with relapsed or progressive low-grade glioma and advance solid tumors (FIREFLY-1). Patent NCT04775485 2023
  44. van Tilburg C.M. Kilburn L.B. Perreault S. Schmidt R. Azizi A.A. Cruz-Martínez O. Zápotocký M. Scheinemann K. Meeteren A.Y.N.S. Sehested A. Opocher E. Driever P.H. Avula S. Ziegler D.S. Capper D. Koch A. Sahm F. Qiu J. Tsao L.P. Blackman S.C. Manley P. Milde T. Witt R. Jones D.T.W. Hargrave D. Witt O. LOGGIC/FIREFLY-2: A phase 3, randomized trial of tovorafenib vs. chemotherapy in pediatric and young adult patients with newly diagnosed low-grade glioma harboring an activating RAF alteration. BMC Cancer 2024 24 1 147 10.1186/s12885‑024‑11820‑x 38291372
    [Google Scholar]
  45. Chen W. Cossrow J. Franklin L. Guan B. Jones J.H. Kumaravel G. Lane B. Littke A. Lugovskoy A. Peng H. Powell N. Raimundo B. Tanaka H. Vessels J. Wynn T. Xin Z. Compounds useful as Raf kinase inhibitors. Patent US8802657B2 2014
  46. Ser M.H. Webb M. Thomsen A. Sener U. Isocitrate dehydrogenase inhibitors in glioma: From bench to bedside. Pharmaceuticals 2024 17 6 682 10.3390/ph17060682 38931350
    [Google Scholar]
  47. Lamb Y.N. Vorasidenib: First approval. Drugs 2024 84 10 1325 1331 10.1007/s40265‑024‑02097‑2 39375303
    [Google Scholar]
  48. Mandonnet E. Delattre J.Y. Tanguy M.L. Swanson K.R. Carpentier A.F. Duffau H. Cornu P. Van Effenterre R. Alvord E.C. Jr Capelle L. Continuous growth of mean tumor diameter in a subset of grade II gliomas. Ann. Neurol. 2003 53 4 524 528 10.1002/ana.10528 12666121
    [Google Scholar]
  49. Rees J. Watt H. Jäger H.R. Benton C. Tozer D. Tofts P. Waldman A. Volumes and growth rates of untreated adult low-grade gliomas indicate risk of early malignant transformation. Eur. J. Radiol. 2009 72 1 54 64 10.1016/j.ejrad.2008.06.013 18632238
    [Google Scholar]
  50. Miller J.J. Gonzalez Castro L.N. McBrayer S. Weller M. Cloughesy T. Portnow J. Andronesi O. Barnholtz-Sloan J.S. Baumert B.G. Berger M.S. Bi W.L. Bindra R. Cahill D.P. Chang S.M. Costello J.F. Horbinski C. Huang R.Y. Jenkins R.B. Ligon K.L. Mellinghoff I.K. Nabors L.B. Platten M. Reardon D.A. Shi D.D. Schiff D. Wick W. Yan H. von Deimling A. van den Bent M. Kaelin W.G. Wen P.Y. Isocitrate dehydrogenase (IDH) mutant gliomas: A Society for Neuro-Oncology (SNO) consensus review on diagnosis, management, and future directions. Neuro-oncol. 2023 25 1 4 25 10.1093/neuonc/noac207 36239925
    [Google Scholar]
  51. FDA approves vorasidenib for grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation. 2024 Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-vorasidenib-grade-2-astrocytoma-or-oligodendroglioma-susceptible-idh1-or-idh2-mutation
  52. Mellinghoff I.K. van den Bent M.J. Blumenthal D.T. Touat M. Peters K.B. Clarke J. Mendez J. Yust-Katz S. Welsh L. Mason W.P. Ducray F. Umemura Y. Nabors B. Holdhoff M. Hottinger A.F. Arakawa Y. Sepulveda J.M. Wick W. Soffietti R. Perry J.R. Giglio P. de la Fuente M. Maher E.A. Schoenfeld S. Zhao D. Pandya S.S. Steelman L. Hassan I. Wen P.Y. Cloughesy T.F. Vorasidenib in IDH1- or IDH2-mutant low-grade glioma. N. Engl. J. Med. 2023 389 7 589 601 10.1056/NEJMoa2304194 37272516
    [Google Scholar]
  53. Study of vorasidenib (AG-881) in Participants with residual or recurrent grade 2 glioma with an IDH1 or IDH2 mutation (INDIGO). Patent NCT04164901 2025
  54. New analyses from pivotal phase 3 indigo study reinforce vorasidenib's potential to change the treatment paradigm for IDH-mutant diffuse glioma. 2023 Available from: https://www.prnewswire.com/news-releases/new-analyses-from-pivotal-phase-3-indigo-study-reinforce-vorasidenibs-potential-to-change-the-treatment-paradigm-for-idh-mutant-diffuse-glioma-301992384.html
  55. Zenon D. Jeneta P.-M. Jeremy M.T. Robert Z. Zhenwei C. Ding Z. Therapeutically active compounds and their methods of use. Patent WO2015003640A1 2015
  56. Benjamin S L. Chong-Hui G. Pharmaceutical compositions thereof, and methods of treatment involving same. Patent WO2019090059A1 2019
  57. Drug trials snapshots: LIVDELZI. 2024 Available from: https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-livdelzi
  58. Hirschfield G.M. Shiffman M.L. Gulamhusein A. Kowdley K.V. Vierling J.M. Levy C. Kremer A.E. Zigmond E. Andreone P. Gordon S.C. Bowlus C.L. Lawitz E.J. Aspinall R.J. Pratt D.S. Raikhelson K. Gonzalez-Huezo M.S. Heneghan M.A. Jeong S.H. Ladrón de Guevara A.L. Mayo M.J. Dalekos G.N. Drenth J.P.H. Janczewska E. Leggett B.A. Nevens F. Vargas V. Zuckerman E. Corpechot C. Fassio E. Hinrichsen H. Invernizzi P. Trivedi P.J. Forman L. Jones D.E.J. Ryder S.D. Swain M.G. Steinberg A. Boudes P.F. Choi Y.J. McWherter C.A. Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study. Hepatology 2023 78 2 397 415 10.1097/HEP.0000000000000395 37386786
    [Google Scholar]
  59. Hirschfield G.M. Bowlus C.L. Mayo M.J. Kremer A.E. Vierling J.M. Kowdley K.V. Levy C. Villamil A. Ladrón de Guevara Cetina A.L. Janczewska E. Zigmond E. Jeong S.H. Yilmaz Y. Kallis Y. Corpechot C. Buggisch P. Invernizzi P. Londoño Hurtado M.C. Bergheanu S. Yang K. Choi Y.J. Crittenden D.B. McWherter C.A. A phase 3 trial of seladelpar in primary biliary cholangitis. N. Engl. J. Med. 2024 390 9 783 794 10.1056/NEJMoa2312100 38381664
    [Google Scholar]
  60. Jones D. Boudes P.F. Swain M.G. Bowlus C.L. Galambos M.R. Bacon B.R. Doerffel Y. Gitlin N. Gordon S.C. Odin J.A. Sheridan D. Wörns M.A. Clark V. Corless L. Hartmann H. Jonas M.E. Kremer A.E. Mells G.F. Buggisch P. Freilich B.L. Levy C. Vierling J.M. Bernstein D.E. Hartleb M. Janczewska E. Rochling F. Shah H. Shiffman M.L. Smith J.H. Choi Y.J. Steinberg A. Varga M. Chera H. Martin R. McWherter C.A. Hirschfield G.M. Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: A double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study. Lancet Gastroenterol. Hepatol. 2017 2 10 716 726 10.1016/S2468‑1253(17)30246‑7 28818518
    [Google Scholar]
  61. Caines A. Trudeau S. Gordon S.C. Evaluating the safety and efficacy of seladelpar for adults with primary biliary cholangitis. Expert Opin. Pharmacother. 2024 25 11 1517 1523 10.1080/14656566.2024.2390120 39107982
    [Google Scholar]
  62. Gee-Hong K. Rui Z. Aihua W. Alan R. D. 4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs. Patent WO2005042478A2 2005
  63. Zhang R. Wang A. DeAngelis A. Pelton P. Xu J. Zhu P. Zhou L. Demarest K. Murray W.V. Kuo G.H. Discovery of para-alkylthiophenoxyacetic acids as a novel series of potent and selective PPARδ agonists. Bioorg. Med. Chem. Lett. 2007 17 14 3855 3859 10.1016/j.bmcl.2007.05.007 17524639
    [Google Scholar]
  64. Maddahi J. Lazewatsky J. Udelson J.E. Berman D.S. Beanlands R.S.B. Heller G.V. Bateman T.M. Knuuti J. Orlandi C. Phase-III clinical trial of fluorine-18 flurpiridaz positron emission tomography for evaluation of coronary artery disease. J. Am. Coll. Cardiol. 2020 76 4 391 401 10.1016/j.jacc.2020.05.063 32703509
    [Google Scholar]
  65. Maddahi J. Agostini D. Bateman T.M. Bax J.J. Beanlands R.S.B. Berman D.S. Dorbala S. Garcia E.V. Feldman J. Heller G.V. Knuuti J.M. Martinez-Clark P. Pelletier-Galarneau M. Shepple B. Tamaki N. Tranquart F. Udelson J.E. Flurpiridaz F18 PET myocardial perfusion imaging in patients with suspected coronary artery disease. J. Am. Coll. Cardiol. 2023 82 16 1598 1610 10.1016/j.jacc.2023.08.016 37821170
    [Google Scholar]
  66. Simon P.R. David S.C. Ming Y. Mikhail K. Joel L. Contrast agents for applications including perfusion imaging. Patent WO2009108376A2 2009
  67. David S. C. Cesati R. Cheesman E.H. Methods of making radiolabeled tracers and precursors thereof. Patent US20070036716A1 2007
  68. FDA approves inavolisib with palbociclib and fulvestrant for endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, advanced breast cancer. 2024 Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-inavolisib-palbociclib-and-fulvestrant-endocrine-resistant-pik3ca-mutated-hr-positive?utm_
  69. Hong R. Edgar K. Song K. Steven S. Young A. Hamilton P. Arrazate A. De La Cruz C. Chan C. Pang J. Salphati L. Belvin M. Nannini M. Staben S. Friedman L. Sampath D. Abstract PD4-14: GDC-0077 is a selective PI3Kα inhibitor that demonstrates robust efficacy in PIK3CA mutant breast cancer models as a single agent and in combination with standard of care therapies. Cancer Res 2018 78 4 Supplement PD4-14 PD4-14 10.1158/1538‑7445.SABCS17‑PD4‑14
    [Google Scholar]
  70. Turner N.C. Im S.A. Saura C. Juric D. Loibl S. Kalinsky K. Schmid P. Loi S. Sunpaweravong P. Musolino A. Li H. Zhang Q. Nowecki Z. Leung R. Thanopoulou E. Shankar N. Lei G. Stout T.J. Hutchinson K.E. Schutzman J.L. Song C. Jhaveri K.L. Inavolisib-based therapy in PIK3CA -mutated advanced breast cancer. N. Engl. J. Med. 2024 391 17 1584 1596 10.1056/NEJMoa2404625 39476340
    [Google Scholar]
  71. André F. Ciruelos E. Rubovszky G. Campone M. Loibl S. Rugo H.S. Iwata H. Conte P. Mayer I.A. Kaufman B. Yamashita T. Lu Y.S. Inoue K. Takahashi M. Pápai Z. Longin A.S. Mills D. Wilke C. Hirawat S. Juric D. Alpelisib for PIK3CA -mutated, hormone receptor–positive advanced breast cancer. N. Engl. J. Med. 2019 380 20 1929 1940 10.1056/NEJMoa1813904 31091374
    [Google Scholar]
  72. He Y. Sun M.M. Zhang G.G. Yang J. Chen K.S. Xu W.W. Li B. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct. Target. Ther. 2021 6 1 425 10.1038/s41392‑021‑00828‑5 34916492
    [Google Scholar]
  73. Schwartzberg L.S. Vidal G.A. Targeting PIK3CA alterations in hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: New therapeutic approaches and practical considerations. Clin. Breast Cancer 2020 20 4 e439 e449 10.1016/j.clbc.2020.02.002 32278641
    [Google Scholar]
  74. Fanucci K. Giordano A. Erick T. Tolaney S.M. Sammons S. Practical treatment strategies and novel therapies in the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway in hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2−) advanced breast cancer. ESMO Open 2024 9 12 103997 10.1016/j.esmoop.2024.103997 39674130
    [Google Scholar]
  75. Comprehensive molecular portraits of human breast tumours. Nature 2012 490 7418 61 70 10.1038/nature11412 23000897
    [Google Scholar]
  76. Mollon L. Aguilar A. Anderson E. Dean J. Davis L. Warholak T. Aizer A.A. Platt E. Bardiya A. Tang D. Abstract 1207: A systematic literature review of the prevalence of PIK3CA mutations and mutation hotspots in HR+/HER2- metastatic breast cancer. Cancer Res. 2018 78 13_Supplement 1207 1207 10.1158/1538‑7445.AM2018‑1207
    [Google Scholar]
  77. Goncalves M.D. Hopkins B.D. Cantley L.C. Phosphatidylinositol 3-kinase, growth disorders, and cancer. N. Engl. J. Med. 2018 379 21 2052 2062 10.1056/NEJMra1704560 30462943
    [Google Scholar]
  78. A study evaluating the efficacy and safety of inavolisib + palbociclib + fulvestrant vs placebo + palbociclib + fulvestrant in patients with PIK3CA-mutant, hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer (INAVO120). 2025 Available from: https://classic.clinicaltrials.gov/ct2/show/NCT04191499
  79. Killock D. First-line triplet therapy for advanced-stage PIK3CA-mutant HR + breast cancer improves outcomes. Nat. Rev. Clin. Oncol. 2025 22 1 1 1 10.1038/s41571‑024‑00968‑x 39533051
    [Google Scholar]
  80. Hoffmann-La F. Roche A.G. Benzoxazepin oxazolidinone compounds and methods of use. Patent WO2017001645A1 2017
  81. Hoffmann-La F. Roche A.G. Process for the preparation Of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4] oxazepin-9-yl)amino) propanamide. Patent WO2018109204A1 2018
  82. Angelaud R. Bruetsch T. Gosselin F. Han C. Stutz A. Process for the preparation of benzoxazepin oxazolidinone compounds. Patent WO2022251567A1 2022
  83. Hanan E.J. Braun M.G. Heald R.A. MacLeod C. Chan C. Clausen S. Edgar K.A. Eigenbrot C. Elliott R. Endres N. Friedman L.S. Gogol E. Gu X.H. Thibodeau R.H. Jackson P.S. Kiefer J.R. Knight J.D. Nannini M. Narukulla R. Pace A. Pang J. Purkey H.E. Salphati L. Sampath D. Schmidt S. Sideris S. Song K. Sujatha-Bhaskar S. Ultsch M. Wallweber H. Xin J. Yeap S. Young A. Zhong Y. Staben S.T. Discovery of GDC-0077 (Inavolisib), a highly selective inhibitor and degrader of mutant PI3Kα. J. Med. Chem. 2022 65 24 16589 16621 10.1021/acs.jmedchem.2c01422 36455032
    [Google Scholar]
  84. Dreijerink K.M.A. Timmers H.T.M. Brown M. Twenty years of menin: Emerging opportunities for restoration of transcriptional regulation in MEN1. Endocr. Relat. Cancer 2017 24 10 T135 T145 10.1530/ERC‑17‑0281 28811299
    [Google Scholar]
  85. Issa G.C. Ravandi F. DiNardo C.D. Jabbour E. Kantarjian H.M. Andreeff M. Therapeutic implications of menin inhibition in acute leukemias. Leukemia 2021 35 9 2482 2495 10.1038/s41375‑021‑01309‑y 34131281
    [Google Scholar]
  86. Meyer C. Larghero P. Almeida Lopes B. Burmeister T. Gröger D. Sutton R. Venn N.C. Cazzaniga G. Corral Abascal L. Tsaur G. Fechina L. Emerenciano M. Pombo-de-Oliveira M.S. Lund-Aho T. Lundán T. Montonen M. Juvonen V. Zuna J. Trka J. Ballerini P. Lapillonne H. Van der Velden V.H.J. Sonneveld E. Delabesse E. de Matos R.R.C. Silva M.L.M. Bomken S. Katsibardi K. Keernik M. Grardel N. Mason J. Price R. Kim J. Eckert C. Lo Nigro L. Bueno C. Menendez P. zur Stadt U. Gameiro P. Sedék L. Szczepański T. Bidet A. Marcu V. Shichrur K. Izraeli S. Madsen H.O. Schäfer B.W. Kubetzko S. Kim R. Clappier E. Trautmann H. Brüggemann M. Archer P. Hancock J. Alten J. Möricke A. Stanulla M. Lentes J. Bergmann A.K. Strehl S. Köhrer S. Nebral K. Dworzak M.N. Haas O.A. Arfeuille C. Caye-Eude A. Cavé H. Marschalek R. The KMT2A recombinome of acute leukemias in 2023. Leukemia 2023 37 5 988 1005 10.1038/s41375‑023‑01877‑1 37019990
    [Google Scholar]
  87. Issa G.C. Bidikian A. Venugopal S. Konopleva M. DiNardo C.D. Kadia T.M. Borthakur G. Jabbour E. Pemmaraju N. Yilmaz M. Short N.J. Maiti A. Sasaki K. Masarova L. Pierce S. Takahashi K. Tang G. Loghavi S. Patel K. Andreeff M. Bhalla K. Garcia-Manero G. Ravandi F. Kantarjian H. Daver N. Clinical outcomes associated with NPM1 mutations in patients with relapsed or refractory AML. Blood Adv. 2023 7 6 933 942 10.1182/bloodadvances.2022008316 36322818
    [Google Scholar]
  88. Yokoyama A. Somervaille T.C.P. Smith K.S. Rozenblatt-Rosen O. Meyerson M. Cleary M.L. The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis. Cell 2005 123 2 207 218 10.1016/j.cell.2005.09.025 16239140
    [Google Scholar]
  89. Grembecka J. He S. Shi A. Purohit T. Muntean A.G. Sorenson R.J. Showalter H.D. Murai M.J. Belcher A.M. Hartley T. Hess J.L. Cierpicki T. Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. Nat. Chem. Biol. 2012 8 3 277 284 10.1038/nchembio.773 22286128
    [Google Scholar]
  90. Kühn M.W.M. Song E. Feng Z. Sinha A. Chen C.W. Deshpande A.J. Cusan M. Farnoud N. Mupo A. Grove C. Koche R. Bradner J.E. de Stanchina E. Vassiliou G.S. Hoshii T. Armstrong S.A. Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia. Cancer Discov. 2016 6 10 1166 1181 10.1158/2159‑8290.CD‑16‑0237 27535106
    [Google Scholar]
  91. Issa G.C. Aldoss I. DiPersio J. Cuglievan B. Stone R. Arellano M. Thirman M.J. Patel M.R. Dickens D.S. Shenoy S. Shukla N. Kantarjian H. Armstrong S.A. Perner F. Perry J.A. Rosen G. Bagley R.G. Meyers M.L. Ordentlich P. Gu Y. Kumar V. Smith S. McGeehan G.M. Stein E.M. The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia. Nature 2023 615 7954 920 924 10.1038/s41586‑023‑05812‑3 36922593
    [Google Scholar]
  92. Salman M.Y. Stein E.M. Revumenib for patients with acute leukemia: A new tool for differentiation therapy. Haematologica 2024 109 11 3488 3495 10.3324/haematol.2022.282621 39086307
    [Google Scholar]
  93. Issa G.C. Aldoss I. Thirman M.J. DiPersio J. Arellano M. Blachly J.S. Mannis G.N. Perl A. Dickens D.S. McMahon C.M. Traer E. Zwaan C.M. Grove C.S. Stone R. Shami P.J. Mantzaris I. Greenwood M. Shukla N. Cuglievan B. Kovacsovics T. Gu Y. Bagley R.G. Madigan K. Chudnovsky Y. Nguyen H.V. McNeer N. Stein E.M. Wei A. Fleming S. Sabins H. Aldoss I. Kovacsovics T. Stone R. Arellano M. Patel M. Talati C. Chen J. Nachmias B. Heiblig M. Fernandez P.M. Arnan-Sangerman M. Stein E.M. Mantzaris I. Blachly J.S. Traer E. Zwaan C.M. Wolach O. Marconi G. Bajel A. Grove C.S. Mannis G.N. Schuh A. Thirman M. Byrd J. McMahon C.M. Dickens D.S. Perl A. Greenwood M. Issa G.C. Whitlock J. Shami P.J. DiPersio J. Menin inhibition with revumenib for KMT2A -rearranged relapsed or refractory acute leukemia (AUGMENT-101). J. Clin. Oncol. 2025 43 1 75 84 10.1200/JCO.24.00826 39121437
    [Google Scholar]
  94. A study of revumenib in R/R leukemias including those with an MLL/KMT2A gene rearrangement or NPM1 mutation (AUGMENT-101). Patent NCT04065399 2024
  95. FDA approves revumenib for relapsed or refractory acute leukemia with a KMT2A translocation. 2024 Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-revumenib-relapsed-or-refractory-acute-leukemia-kmt2a-translocation
  96. Cacatian S. Claremon D.A. Dillard L.W. Dong C. Fan Y. Jia L. Lotesta S.D. Marcus A. Morales-Ramos A. Singh S.B. Venkatraman S. Yuan J. Zheng Y. Zhuang L. Parent S.D. Houston T.L. Preparation of inhibitors of the menin-MLL interaction. Patent WO2017214367A1 2017
  97. Younis M. Ogbu I. Kalra D.K. Optimizing drug therapies in cardiac amyloidosis. Pharmacol. Ther. 2025 265 108758 10.1016/j.pharmthera.2024.108758 39586360
    [Google Scholar]
  98. Gillmore J.D. Judge D.P. Cappelli F. Fontana M. Garcia-Pavia P. Gibbs S. Grogan M. Hanna M. Hoffman J. Masri A. Maurer M.S. Nativi-Nicolau J. Obici L. Poulsen S.H. Rockhold F. Shah K.B. Soman P. Garg J. Chiswell K. Xu H. Cao X. Lystig T. Sinha U. Fox J.C. Efficacy and safety of acoramidis in transthyretin amyloid cardiomyopathy. N. Engl. J. Med. 2024 390 2 132 142 10.1056/NEJMoa2305434 38197816
    [Google Scholar]
  99. Hellenbart E.L. Ipema H.J. Rodriguez‐Ziccardi M.C. Krishna H. DiDomenico R.J. Disease-modifying therapies for amyloid transthyretin cardiomyopathy: Current and emerging medications. Pharmacotherapy 2025 45 2 124 144 10.1002/phar.4639 39714070
    [Google Scholar]
  100. Griffin J.M. Rosenblum H. Maurer M.S. Pathophysiology and therapeutic approaches to cardiac amyloidosis. Circ. Res. 2021 128 10 1554 1575 10.1161/CIRCRESAHA.121.318187 33983835
    [Google Scholar]
  101. Judge D.P. Heitner S.B. Falk R.H. Maurer M.S. Shah S.J. Witteles R.M. Grogan M. Selby V.N. Jacoby D. Hanna M. Nativi-Nicolau J. Patel J. Rao S. Sinha U. Turtle C.W. Fox J.C. Transthyretin stabilization by AG10 in symptomatic transthyretin amyloid cardiomyopathy. J. Am. Coll. Cardiol. 2019 74 3 285 295 10.1016/j.jacc.2019.03.012 30885685
    [Google Scholar]
  102. Graef I.A. Alhamadsheh M.M. Compounds and compositions that bind and stabilize transthyretin and their use for inhibiting transthyretin amyloidosis and protein-protein interactions. Patent US009913826B2 2018
  103. Newfield R.S. Sarafoglou K. Fechner P.Y. Nokoff N.J. Auchus R.J. Vogiatzi M.G. Jeha G.S. Giri N. Roberts E. Sturgeon J. Chan J.L. Farber R.H. Crinecerfont, a CRF1 receptor antagonist, lowers adrenal androgens in adolescents with congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 2023 108 11 2871 2878 10.1210/clinem/dgad270 37216921
    [Google Scholar]
  104. FDA approves new treatment for congenital adrenal hyperplasia. 2024 Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-congenital-adrenal-hyperplasia?utm_
  105. Claahsen - Van Der Grinten H. L. Speiser P. W. Ahmed S. F. Arlt W. Auchus R. J. Falhammar H. Flück C. E. Guasti L. Huebner A. Kortmann B. B. M. Krone N. Merke D. P. Miller W. L. Nordenström A. Reisch N. Sandberg D. E. Stikkelbroeck N. M. M. L. Touraine P. Utari A. Wudy S. A. White P. C. Congenital adrenal hyperplasia—current insights in pathophysiology, diagnostics, and management. Endocr. Rev. 2022 43 91 159
    [Google Scholar]
  106. Kamrath C. Wettstaedt L. Boettcher C. Hartmann M.F. Wudy S.A. Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia. J. Steroid Biochem. Mol. Biol. 2018 178 221 228 10.1016/j.jsbmb.2017.12.016 29277706
    [Google Scholar]
  107. Turcu A.F. Nanba A.T. Chomic R. Upadhyay S.K. Giordano T.J. Shields J.J. Merke D.P. Rainey W.E. Auchus R.J. Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency. Eur. J. Endocrinol. 2016 174 5 601 609 10.1530/EJE‑15‑1181 26865584
    [Google Scholar]
  108. Sarafoglou K. Kim M.S. Lodish M. Felner E.I. Martinerie L. Nokoff N.J. Clemente M. Fechner P.Y. Vogiatzi M.G. Speiser P.W. Auchus R.J. Rosales G.B.G. Roberts E. Jeha G.S. Farber R.H. Chan J.L. Phase 3 trial of crinecerfont in pediatric congenital adrenal hyperplasia. N. Engl. J. Med. 2024 391 6 493 503 10.1056/NEJMoa2404655 38828945
    [Google Scholar]
  109. Auchus R.J. Sarafoglou K. Fechner P.Y. Vogiatzi M.G. Imel E.A. Davis S.M. Giri N. Sturgeon J. Roberts E. Chan J.L. Farber R.H. Crinecerfont lowers elevated hormone markers in adults with 21-hydroxylase deficiency congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 2022 107 3 801 812 10.1210/clinem/dgab749 34653252
    [Google Scholar]
  110. Robert H.F. Gordon R.L. Xiaoping Z. Nagdeep G. Crf1 receptor antagonist, pharmaceutical formulations and solid forms thereof for the treatment of congenital adrenal hyperplasia. Patent WO2020115555A2 2020
  111. Andrew P. Scott S. Joel R. Synthetic methods for preparation ff 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-l-(3-fluoro-4 methylphenyl) ethyl]-5-methyl-v-prop-2-ynyl-l,3-thiazol-2-amine. Patent US12128033B2 2021
  112. Horn L. Infante J.R. Reckamp K.L. Blumenschein G.R. Leal T.A. Waqar S.N. Gitlitz B.J. Sanborn R.E. Whisenant J.G. Du L. Neal J.W. Gockerman J.P. Dukart G. Harrow K. Liang C. Gibbons J.J. Holzhausen A. Lovly C.M. Wakelee H.A. Ensartinib (X-396) in ALK-positive non–small cell lung cancer: Results from a first-in-human phase I/II, multicenter study. Clin. Cancer Res. 2018 24 12 2771 2779 10.1158/1078‑0432.CCR‑17‑2398 29563138
    [Google Scholar]
  113. Duma N. Santana-Davila R. Molina J.R. Non–small cell lung cancer: Epidemiology, screening, diagnosis, and treatment. Mayo Clin. Proc. 2019 94 8 1623 1640 10.1016/j.mayocp.2019.01.013 31378236
    [Google Scholar]
  114. Soda M. Choi Y.L. Enomoto M. Takada S. Yamashita Y. Ishikawa S. Fujiwara S. Watanabe H. Kurashina K. Hatanaka H. Bando M. Ohno S. Ishikawa Y. Aburatani H. Niki T. Sohara Y. Sugiyama Y. Mano H. Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer. Nature 2007 448 7153 561 566 10.1038/nature05945 17625570
    [Google Scholar]
  115. Shaw A.T. Solomon B. Targeting anaplastic lymphoma kinase in lung cancer. Clin. Cancer Res. 2011 17 8 2081 2086 10.1158/1078‑0432.CCR‑10‑1591 21288922
    [Google Scholar]
  116. FDA approves ensartinib for ALK-positive locally advanced or metastatic non-small cell lung cancer. 2024 Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ensartinib-alk-positive-locally-advanced-or-metastatic-non-small-cell-lung-cancer
  117. Horn L. Wang Z. Wu G. Poddubskaya E. Mok T. Reck M. Wakelee H. Chiappori A.A. Lee D.H. Breder V. Orlov S. Cicin I. Cheng Y. Liu Y. Fan Y. Whisenant J.G. Zhou Y. Oertel V. Harrow K. Liang C. Mao L. Selvaggi G. Wu Y.L. Ensartinib vs crizotinib for patients with anaplastic lymphoma kinase−positive non–small cell lung cancer. JAMA Oncol. 2021 7 11 1617 1625 10.1001/jamaoncol.2021.3523 34473194
    [Google Scholar]
  118. Bellur S. Khosla A.A. Ozair A. Kotecha R. McDermott M.W. Ahluwalia M.S. Management of brain metastases: A review of novel therapies. Semin. Neurol. 2023 43 6 845 858 10.1055/s‑0043‑1776782 38011864
    [Google Scholar]
  119. Luo Y. Zhang Z. Guo X. Tang X. Li S. Gong G. Gao S. Zhang Y. Lin S. Comparative safety of anaplastic lymphoma kinase tyrosine kinase inhibitors in advanced anaplastic lymphoma kinase-mutated non-small cell lung cancer: Systematic review and network meta-analysis. Lung Cancer 2023 184 107319 10.1016/j.lungcan.2023.107319 37597303
    [Google Scholar]
  120. Horn L. Wu Y.L. Reck M. Wakelee H.A. Liang C. Tan F. Harrow K. Oertel V. Dukart G. Mok T. eXalt3: Phase 3 randomized study comparing ensartinib to crizotinib in anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) patients. J. Clin. Oncol. 2018 36 15_suppl TPS9115 TPS9115 10.1200/JCO.2018.36.15_suppl.TPS9115
    [Google Scholar]
  121. Soria J.C. Tan D.S.W. Chiari R. Wu Y.L. Paz-Ares L. Wolf J. Geater S.L. Orlov S. Cortinovis D. Yu C.J. Hochmair M. Cortot A.B. Tsai C.M. Moro-Sibilot D. Campelo R.G. McCulloch T. Sen P. Dugan M. Pantano S. Branle F. Massacesi C. de Castro G. Jr First-line ceritinib versus platinum-based chemotherapy in advanced ALK -rearranged non-small-cell lung cancer (ASCEND-4): A randomised, open-label, phase 3 study. Lancet 2017 389 10072 917 929 10.1016/S0140‑6736(17)30123‑X 28126333
    [Google Scholar]
  122. Mastrantoni L. Giordano G. Vita E. Horn G. Russo J. Orlandi A. Daniele G. Giannarelli D. Tortora G. Bria E. The likelihood of being helped or harmed as a patient-centred tool to assess ALK-Inhibitors clinical impact and safety in ALK-addicted non-small cell lung cancer: A systematic review and sensitivity-analysis. Cancer Treat. Res. Commun. 2024 41 100842 10.1016/j.ctarc.2024.100842 39260066
    [Google Scholar]
  123. Liang C. Substituted pyridazine carboxamide compounds. Patent US20130190298A1 2013
  124. Gao H. Zhang J.Y. Zhao L.J. Guo Y.Y. Synthesis and clinical application of small-molecule inhibitors and PROTACs of anaplastic lymphoma kinase. Bioorg. Chem. 2023 140 106807 10.1016/j.bioorg.2023.106807 37651895
    [Google Scholar]
  125. Vertex announces US FDA approval of ALYFTREK™, a once-daily next-in-class cftr modulator for the treatment of cystic fibrosis. 2024 Available from: https://www.businesswire.com/news/home/20241220133127/en/Vertex-Announces-US-FDA-Approval-of-ALYFTREK%E2%84%A2-a-Once-Daily-Next-in-Class-CFTR-Modulator-for-the-Treatment-of-Cystic-Fibrosis
  126. FDA approves new, once-a-day CFTR modulator for people with CF. 2024 Available from: https://www.cff.org/news/2024-12/fda-approves-new-cftr-modulator#:~:text=The%20U.S.%20Food%20and,a%20modulator.&text=triple%2Dcombination%20modulator%20Alyftrek%20%28vanzacaftor%2Ftezacaftor%2Fdeutivacaftor%29,a%20modulator.&text=older%20who%20have%20a,a%20modulator.&text=one%20of%2031%20rare,a%20modulator
  127. FDA approves alyftrek, once-daily CFTR modulator for cystic fibrosis. 2024 Available from: https://www.pharmacytimes.com/view/fda-approves-alyftrek-once-daily-cftr-modulator-for-cystic-fibrosis
  128. Keating C. Yonker L. Vermeulen F. Prais D. Linnemann R. Trimble A. Kotsimbos T. Mermis J. Braun A. O’Carroll M. Sutharsan S. Ramsey B. Mall M. Taylor-Cousar J. McKone E. Tullis E. Floreth T. Michelson P. Nair N. Yi B. Martin H. Ahluwalia N. Lam A. Horsley A. 120 Vanzacaftor/tezacaftor/deutivacaftor in adolescents and adults with cystic fibrosis: Results from two randomized, active-controlled phase 3 trials. J. Cyst. Fibros. 2024 23 S63 S64 10.1016/S1569‑1993(24)00962‑7
    [Google Scholar]
  129. Kolski-Andreaco A. Taiclet S. Myerburg M.M. Sembrat J. Bridges R.J. Straub A.C. Wills Z.P. Butterworth M.B. Devor D.C. Potentiation of BKCa channels by cystic fibrosis transmembrane conductance regulator correctors VX-445 and VX-121. J. Clin. Invest. 2024 134 16 e176328 10.1172/JCI176328 38954478
    [Google Scholar]
  130. A phase 3 study of vx-121 combination therapy in participants with cystic fibrosis (CF) heterozygous for F508del and a minimal function mutation (F/MF). Patent NCT05033080 2024
  131. A study of VX-121 combination therapy in participants with cystic fibrosis (CF) who are homozygous for F508del, heterozygous for f508del and a gating (F/G) or residual function (F/RF) mutation, or have at least 1 other triple combination responsive (TCR) CFTR mutation and no F508del mutation. Patent NCT05076149 2024
  132. Uluer A.Z. MacGregor G. Azevedo P. Indihar V. Keating C. Mall M.A. McKone E.F. Ramsey B.W. Rowe S.M. Rubenstein R.C. Taylor-Cousar J.L. Tullis E. Yonker L.M. Chu C. Lam A.P. Nair N. Sosnay P.R. Tian S. Van Goor F. Viswanathan L. Waltz D. Wang L.T. Xi Y. Billings J. Horsley A. Horsley A. Nash E.F. Bakker M. van der Meer R. Merkus P. Majoor C. McCoy K. Billings J. Pancham K. Tolle J. Quick B. Uluer A. DiMango E. Rao A. Reyes S. Klingsberg R. Barreto C. Ortega V. Willey-Courand D. Schwarz C. Sutharsan S. Fischer R. Davies J. Duckers J. Horsley A. Doe S. Nash E.F. Bakker M. Heijerman H. van der Meer R. Merkus P. Majoor C. Solomon G.M. Merlo C. Griffonnet J. Pilewski J. Dunitz J. Sheikh S. Rubenstein R.C. Rosenbluth D.B. Liou T. Indihar M. Pancham K. Yonker L. Nasr S. Griffonnet J. Brown C.D. Sawicki G.S. Ruddy J. DiMango E. Garcia B. Braun A. Gifford A.H. Mehdi N. Tupayachi Ortiz M. Jain R. Calimano F.J. Johannes J. Daines C.L. Fullmer J. Mermis J. Barrios C. Ly N. Casserly B.P. Eisenmann S. Hebestreit H. Kiefer A. Sutharsan S. Fischer R. MacGregor G. Peckham D. Ledson M. Van Braeckel E. Merkus P. McElvaney N.G. McKone E. Plant B. Burr L. Smith D.J. Middleton P. Wilson J. Safety and efficacy of vanzacaftor–tezacaftor–deutivacaftor in adults with cystic fibrosis: Randomised, double-blind, controlled, phase 2 trials. Lancet Respir. Med. 2023 11 6 550 562 10.1016/S2213‑2600(22)00504‑5 36842446
    [Google Scholar]
  133. a Ruah S.S.H. Grootenhuis P.D.J. van Goor F. Miller M.T. McCartney J. Zhou J. Bear B.R. Numa M.M.D. Modulators of ATP-binding cassette transporters. U.S. Patent 2010/053471A1 2010
  134. b Ruah S.S.H. Grootenhuis P.D.J. van Goor F.F. Zhou J. Bear B.R. Miller M.T. McCartney J. Numa M.M.D. Modulators of ATP-binding cassette transporters. U.S. Patent 2013/0178471A1 2013
  135. c Ruah S.S.H. Grootenhuis P.D.J. van Goor F.F. Zhou J. Bear B.R. Miller M.T. McCartney J. Numa M.M.D. Indole derivatives as CFTR modulators. U.S. Patent 2009/0131492A1 2009
  136. Alargova R.G. Dunbar C.A. Kadiyala I.N. Pharmaceutical compositions of (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide and administration thereof. U.S. Patent 2014/014841A1 2014
  137. Hughes D.L. Patent review of synthetic routes and crystalline forms of the CFTR-modulator drugs ivacaftor, lumacaftor, tezacaftor, and elexacaftor. Org. Process Res. Dev. 2019 23 11 2302 2322 10.1021/acs.oprd.9b00326
    [Google Scholar]
  138. a Tanoury G.J. Harrison C. Littler B.J. Rose P.J. Hughes R.M. Jung Y.C. Siesel D.A. Lee E.C. Belmont D.T. Process of producing cycloalkylcarboxamide-indole compounds. U.S. Patent 2011/133751 2011
  139. b Tanoury G.J. Harrison C. Littler B.J. Rose P.J. Hughes R.M. Jung Y.C. Siesel D.A. Lee E.C. Belmont D.T. Process of producing cycloalkylcarboxamide-indole compounds. U.S. Patent 10,071,979 2018
  140. Novel drug approvals for 2024. 2024 Available from: https://www.fda.gov/drugs/novel-drug-approvals-fda/novel-drug-approvals-2024
/content/journals/ctmc/10.2174/0115680266388061250917093142
Loading
FDA-Approved Fluorine-Containing Molecules in 2024: Significance, Synthesis, and Therapeutic Applications
Bentham Science Publishers ; https://doi.org/10.2174/0115680266388061250917093142
/content/journals/ctmc/10.2174/0115680266388061250917093142
/content/journals/ctmc/10.2174/0115680266388061250917093142
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.

file format download Download

  • Article Type:     Review Article
Keywords: Medicinal chemistry ; Therapeutic applications ; Drug discovery ; Small-molecule therapeutics ; 2024 FDA-approved drugs ; Fluorinated drugs

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test