Recent Patents on Anti-Infective Drug Discovery - Volume 2, Issue 1, 2007

Severe acute respiratory syndrome (SARS) is an epidemic that spread worldwide in early 2003. The aetiological agent was originally defined as a novel coronavirus and later designated as the SARS coronavirus (SARSCoV), which appears similar to other coronaviruses in both virion structure and genome organization with a singlestranded, plus-sense RNA. However, the epidemiology and pathogenesis of SARS remain poorly understood and there is currently no effective treatment. To date, considerable research has been done on detection, prevention and treatment of SARS. In this review, we mainly focus on the recent patents and research work on detecting, preventing and treating SARS.

In the third decade of the Helicobacter pylori era several informations are available on its pathogenetic mechanisms, as well as on therapeutic approaches. A 7-14 day triple or quadruple regimens (proton pump inhibitor together with 2 antibiotics) are currently suggested as first-line treatment, but the success rate following these therapy is constantly decreasing worldwide. Therefore, new drugs are needed to treat such a widespread infection. Several patents of new antibiotics have been claimed in the last 5 years, and some of them showed a very powerful antibacterial activity in vitro, even against clarithromycin and metronidazole resistant strains. Among the new compounds, thienylthiazole derivatives, benzamide derivatives and pyloricidins should be regarded as very promising molecules.

Chagas disease or American Trypanosomiasis, a parasitic infection typically spread by triatomine bugs, affects millions of people throughout Latin America. Current chemotherapy based on the nitroaromatic compounds, benznidazole and nifurtimox provides unsatisfactory results and suffers from considerable side effects and low efficacy. Therefore, there is an urgent need for new drugs to treat this neglected disease. Over the last two decades, new advances and understanding in the biology and the biochemistry of Trypanosoma cruzi has allowed the identification of multiple targets for Chagas disease chemotherapy. This review summarizes antichagasic agents obtained based on i) target metabolic biochemical pathways or parasite specific enzymes, ii) natural products and its derivatives, iii) design and synthesis of lead compounds. Related patents filed and issued from 2000 to early 2006 are also discussed. Most of them claimed inhibitors on specific parasite targets such as cysteine proteinase, sterol biosynthesis, protein farnesyltransferase, etc. Particularly, those related to cysteine proteinase inhibitors were the most represented. Natural products also displayed many anti-T cruzi lead compounds. In addition, a few patents claiming natural or synthetic compounds with antichagasic activity, disclosed no specific target. However, only a small proportion of all these patents displayed specific data of biological trypanocidal activity.

Cytomegalovirus (CMV) infection is one of the most important infectious complications of solid-organ transplantation, a serious, life-threatining, opportunistic pathogen in HIV-infected patients, and may cause hearing defects and irreversible central nervous system disease in infants infected during gestation. Four drugs are currently licensed for prophylaxis, pre-emptive therapy, and treatment of CMV infection - ganciclovir, and its oral prodrug valganciclovir, foscarnet, cidofovir, and fomivirsen. All four drugs are effective against CMV infection. Toxicities, drug-drug interactions, poor bioaailibility, and the development of drug resistance, however, are clinically relevant and common limitations of these drugs. Novel compounds are on the horizon that possibly will become useful alternatives to currently licensed drugs. Maribavir, a benzimidazol, is the most promising novel drug and closest to clinical application. Several phase II clinical trials proved its good tolerability and effectivity. Other compounds are currently evaluated in pre-clinical and phase I trials with promising preliminary data. In addition, analogs of cidofovir posess significantly improved pharmacological and virological characteristics allowing their oral administration. This review summarizes the current status in drug development and will introduce the most recent patents on this line of research.

Linezolid is the first approved member of a new generation of antibiotics, the synthetic oxazolidinones, to become available, with a broad spectrum of in vitro activity against Gram-positive organisms, including methicillinresistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium. It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children. With regards to its antimicrobial action, linezolid has a predominantly bacteriostatic action, rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics. Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections, both in the community and in a hospital setting. Clinical indications so far include skin and soft tissue infections, communityacquired or nosocomial pneumonia due to MRSA, VRE bacteremia and community-acquired pneumonia due to penicillinresistant Streptococcus pneumoniae. We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far, such as VRE- associated endocarditis, bone and joint multi-drug resistant infections and possibly central nervous system infections, both in adult and children populations. Some patents on linezolid are also discussed in this review.

Clinical trials and clinical studies, using patented drugs and drugs off patent, provide data that impact the best treatment practices for substance abuse and dependence. In the United States, medications have been approved for use in the treatment of both alcohol and opioid dependence. Medications are used in the detoxification from drug abuse and dependence in the symptomatic relief of withdrawal. For long term treatment or medical maintenance treatment, medications eliminate the physiological effects of drug use by blocking drug-receptor binding in the brain. Therefore, patented drugs showing interactions with neurotransmitters in the brain, are attractive candidates for treatment efficacy trials. An effective long term treatment paradigm for reducing drug dependence is the combinatorial use of medications that block the effects of drug use with behavior change counseling and psychotherapy. Medications used for the long term treatment of opioid dependence are methadone, buprenorphine, and naltrexone. Pharmacotherapies used in the treatment of alcohol dependence include acamprosate, antabuse and naltrexone. A reliable indicator for successful treatment of drug dependence is time in treatment. Patients remain in long term treatment when they perceive that their health care environment is supportive and non-stigmatizing and with a good patient-provider relationship where their needs are identified and met. Additional medications are needed for individual comprehensive substance abuse treatment plans, particularly for individuals who abuse stimulants. Patented drugs remain an important source of candidate pharmacotherapies comprising medication assistant treatment, part of a comprehensive treatment plan for drug dependence that addresses the medical, social, and psychological needs of the patient. Adapting this drug treatment paradigm globally requires identifying and testing new drug candidates while building and changing programs to patient centered treatment programs that promote access to care and treatment and integrate medical, psychological, and social services.