Current Topics in Medicinal Chemistry - Volume 6, Issue 5, 2006

A fundamental issue plaguing drug discovery is the high failure rate. Funding of the failed research is a contributor to the high cost of medicines and consequently, the rising cost of health care. How can the failure rate of drug discovery be minimized and the success rate of drug discovery increased? This issue of Current Topics in Medicinal Chemistry takes aim at learning what it takes for success from successful drug discovery. Three case studies and a review article provide insights into the process of successful drug discovery. What factors are important for drug discovery success? Two eminent drug discovers, Dr. Paul Janssen and Sir James Black, both found that a clear concept or idea, a good chemical starting point, time to allow iterative evolution, intense concentration and relentless commitment were the keys to success [1,2]. They believed that lack of commitment and technology driven projects are contributors to failure. The success stories in this issue describe the ideas that initiated the projects, the chemical starting points and the iterative processes used to identify the new medicines. Steven Frye of GSK chronicles the successful path to the discovery of the dual 5α reductase inhibitor dutasteride. He explains the origination of the idea for a once daily dual 5α-reductase inhibitor, the chemical starting point from steroid substrate analogs and past experience with finasteride, and the use of dog as an iterative model to optimize pharmacokinetics. The knowledge gained from experience with finasteride, the first 5α-reductase inhibitor, was used to hypothesize that a dual acting mechanism-based inhibitor is required to achieve greater clinical suppression of dihydrotestosterone and clinical efficacy against benign prostatic hyperplasia. The efforts of the GSK scientists eventually proved the hypothesis correct. Klaus Klumpp and Bradford Graves of Roche describe the discovery of the orally active influenza neuraminidase inhibitor, Tamiflu. Previous influenza neuraminidase inhibitors had high affinity but poor pharmacokinetic properties because of the polar charged character of the binding site. The idea was to find a molecule with less polarity and that still retained the activity. Starting with transition state mimics, they found a subtle conformational change in the active site that exposed a non-polar surface allowing a molecule to have both high binding affinity and drug-like properties. Karen Lackey of GSK recounts the path to discovery of Lapatinib, a dual EGF receptor/ErbB-2 kinase inhibitor currently in phase III studies for cancer. She points out that the idea was to target the two receptors with quinazoline-like compounds. She emphasizes how increased knowledge about the target and chemical series assisted the evolution of the efficacy and mechanism of action assays. A key breakthrough for their work was the discovery of molecules with cellular potency against both isoforms of the EGF receptor. A mathematical index is described which was used to formulate the medicinal chemistry plan. Retrospectively, it was found that these molecules had a unique binding mode to the kinase. These three successful drug discovery examples all have in common a clear idea of what they wished to achieve, good chemical starting points and evolved iterative processes to optimize the drug candidates. Janssen and Black identified the time required for iteration as a potential barrier to success [1,2]. A more rapid iteration may occur when experience from past drug discovery success can be used to guide current research. Past experience can also help define when a compound is sufficiently optimized (when there have been sufficient iterations). A review of the biochemical mechanism of action of new molecular entities approved by the US FDA between 2001 and 2004 suggests that the mechanism of drug action will contribute to a drug's therapeutic index. The potential for mechanism-based toxicity was identified as a key determinant of a drug's mechanism of action. Binding mechanisms will evolve for targets with no mechanism-based toxicity that maximize the effect at the lowest drug concentration by avoiding mass action competition to minimize off-target toxicities, whereas drugs with a potential for mechanism-based toxicity require a mechanism to minimize toxicity while retaining efficacy. Targeting drug targets that have mechanism-based toxicity has a greater risk requiring early iterative optimization of both efficacy and toxicity. Awareness of rules based on past drug discovery experience should facilitate drug discovery by decreasing the time required for the iterative evolution of molecules with the characteristics to be a medicine...........

In this review the preclinical medicinal chemistry, biochemistry and clinical results achieved in the treatment of prostatic disease with dutasteride, a dual inhibitor of type 1 and type 2 5α-reductase are described. During the discovery phase, dutasteride was optimized to inhibit both forms of human 5 α-reductase (5AR) via extensive structure activity relationship studies versus the cloned human isozymes. Dutasteride has subsequently been shown to improve disease measures in patients with symptomatic benign prostatic hyperplasia (BPH) in three randomized, placebo-controlled, Phase III clinical studies lasting for 2 years. Additionally, dutasteride is now under study for the ability to reduce the incidence of prostate cancer in men at high risk of the disease - an indication where the unique dual inhibitor nature, half-life and tolerability of dutasteride may be especially significant factors in determining treatment success. The connections between preclinical drug design and clinical outcomes during the discovery and development of dutasteride are exemplified.

Binding affinity optimization of small molecules interacting with polar binding sites on target proteins is a formidable, but not uncommon challenge in drug discovery. The challenge relates to the difficulty of integrating favourable and unfavourable polar, non-polar and conformation contributions into overall favourable binding energies. This review describes the surprising breakthrough findings leading to the development of Tamiflu, a clinically efficacious orally bioavailable drug targeting the active site of influenza neuraminidase (NA). The NA active site is highly polar and formed mostly by arginine, aspartate and glutamate residues. This active site structure evolved for efficient interaction with charged sialic acid moieties on glycoproteins and stabilization of an oxocarbonium ion in the transition state of the neuraminidase reaction. The initial strategy of optimizing polar interactions in transition state analogs led to NA inhibitors (NAIs) with sub-nanomolar binding affinities, but such compounds were highly polar and lacked oral bioavailability. The realization of the possibility to achieve high affinity binding in a highly polar active site through optimization of non-polar and van-der-Waals interactions initially appeared counterintuitive and required a few serendipitous findings, but was key to reduce the polarity of drug candidates, avoid large desolvation penalties and achieve oral bioavailability.

Protein Kinases offer many opportunities for drug intervention points since phosphorylation is the most common post-translational modification [1]. Phosphorylation regulates activity, location, degradation, conformation and the aberrant activity is implicated in many diseases, including cancer, inflammation, cardiovascular and central nervous system diseases [2-5]. The focus of this review will be on the generation of highly effective signaling inhibitors targeting members of the erbB family of receptor tyrosine kinases, EGFR and ErbB-2, also known as transmembrane Type 1 receptor tyrosine kinases of the HER family of receptors. Ligand binding to the receptor causes a conformational change which activates the tyrosine kinase domain leading to autophosphorylation. This autophosphorylation activates the RAS/mitogen activated protein (MAP) kinase and phosphoinositol-3-kinase (PI3K) pathways leading to a myriad of signaling and cellular activities [6]. Type 1 receptors are over-expressed in a variety of cancers and generally correlate with poor prognosis. For this reason, scientists at GlaxoSmithKline and many others in the scientific community, target the ATP binding site of the intracellular portion of the protein to block the aberrant signaling event. This review intends to cover the lessons learned in the discovery of lapatinib (GW572016, GW2016) by pulling together the various different publications that have been generated in distinct disciplines on aspects of the drug discovery program. Data analyses and correlation of assay data to help with the design of drug like molecules will be included and will demonstrate a break from the traditional focus on absolute potency as a guiding factor in lead compound selection.

The United States FDA approved 85 New Molecular Entities (NMEs) during the period from January 2001 to November 2004 of which 60 were pharmaceuticals with known molecular targets. The majority targeted enzymes (48%) or G-protein coupled receptors (GPCRs) (33%). Eighty percent of the NMEs interacted at the same site as endogenous effector; either as competitive inhibitor/antagonist (67%) or agonist (13%). Three biochemical operations defined the modes of action of the NMEs: 1) mass action competition (equilibrium), 2) a drug stabilized conformational change in the target that is important to the response (conformational) and/or 3) drug action is less-responsive to mass action competition with effectors due to non-equilibrium kinetics (non-equilibrium kinetic). Approximately 80% of the NMEs elicit a response utilizing conformational and/or non-equilibrium kinetic mechanisms. The remaining 20% of NMEs find mass action competition with the endogenous substrate or ligand sufficient for therapeutic utility. These observations indicate that for the majority of drug targets, mass action driven equilibrium binding alone may not be sufficient for maximal therapeutic utility. A key determinant of the biochemical mode of action for these NMEs was to minimize the potential for toxicity, either by providing a maximal response at a low dose to minimize off-target toxicities, or by providing a mechanism to minimize the incidence of mechanism-based toxicity while retaining a sufficiently efficacious response. This principle appears to be independent of target class and provides insight as to intrinsic biochemical features and approaches required for a maximal therapeutic index.

A broad overview is presented describing the current knowledge and the ongoing research concerning the 4- aminoquinolines (4AQ) as chemotherapeutic antimalarial agents. Included are discussions of mechanism of action, structure activity relationships (SAR), chemistry, metabolism and toxicity and parasite resistance mechanisms. In discussions of SAR, particular emphasis has been given to activity versus chloroquine resistant strains of Plasmodium falciparum. Promising new lead compounds undergoing development are described and an overview of physicochemical properties of chloroquine and amodiaquine analogues is also included.

The artemisinin derivatives, dihydroartemisinin (DHA), artesunate, atemether and arteether, are currently used for treatment of malaria in artemisinin combination therapies (ACT) with longer half-life drugs. The demand is enormous - in 2005, the estimated global demand for one such ACT alone, artemether-lumifantrine, which constitutes about 70% of all current clinically-used ACTs, is for 120 million adult treatment courses. At 0.5 gm of artemether per total dose regimen, the amount of artemisinin required is approximately 114 tons. This has placed substantial stress on total artemisinin supplies world-wide, and considerable attention is being focussed on enhancing availability of artemisinin by improvement in horticultural practice and extraction of artemisinin from Artemisia annua. Artemisinic acid, which also occurs in A. annua, can be converted into artemisinin and is the ultimate target of a biotechnological approach, which if successful, will augment artemisinin supply in the future. The conversion of artemisinin into the known artemisinin derivatives, and problems with the methods are critically reviewed. Some attention is paid to mechanistic aspects which clarify stereochemistry. The current artemisinins are by no means ideal drugs. Artesunate in particular is incompatible with basic quinolines by virtue of proton transfer, and has intrinsic chemical instability. At pH 1.2, conversion to DHA is rapid, with t1/2 26 min, and at pH 7.4, t1/2 is about 10 hours. With a pKa of 4.6, over 99% of artesunate will be ionized at pH 7.4, and thus uptake by passive diffusion from the intestinal tract will be minimal. Although a considerable effort has been vested in the search for new artemisinins, largely through functionalization of artemisinin at C-10, O-11 or at C-15 via artemisitene, or of DHA at C-10, deliberate enhancement of the 'druggability' of artemisinins by reducing lipophilicity, which at the same time will attenuate the neurotoxicity characteristic of the current derivatives, and enhance absorption, by and large has not been considered. A review of the various types of newer derivatives is given together with a consideration of medicinal chemistry aspects.

The control of Leishmania infections relies primarily on chemotherapy. The arsenal of drugs available against Leishmania infections is limited and includes pentavalent antimonials, pentamidine, amphotericin B, miltefosine, paromomycin, allopurinol, and few other drugs at various stages of their development process. Knowledge about action and resistance mechanisms involved may allow the development of new drugs that minimise or circumvent drug resistance or may identify new targets for drug development. The aim of this review is to propose some chemical topics to design new modulators from the mechanisms of action of drugs and resistance mechanisms to drugs used in the clinic against Leishmania infections. Thus, different classes of ABC transporters extrude antimonials in Leishmania resulting in drug-resistant phenotypes. Compounds interfering with thiol and polyamine metabolism could be designed to inhibit the antimonial detoxication and therefore, such compounds could be used in combination with antimonials. New diamidines could be synthesized in regard to their ability to inhibit topoisomerase II. The challenge for amphotericin B is to be absorbed by oral route requiring labile physico-chemical modifications. New sesquiterpens and flavonoids have to be developed as reversant of antimonial resistance. Although some studies have focused on developing inhibitors against these resistant phenotypes, new efficient modulators that are able to inhibit drug efflux are needed.