"Inhibitors of HIV-1 Maturation"
Nicholas A. Meanwell, Ph.D., FRSC
Dept. of Chemistry and Molecular Technologies, Bristol-Myers Squibb Research and Development
Abstract: Maturation of the HIV-1 capsid (CA) peptide by HIV-1 protease-mediated cleavage at the CA-SP1 junction is the final step in the formation of infectious virus capsid. A phenotypic screen identified the betulinic acid derivative bevirimat as an inhibitor specific to this step in virion production and this compound demonstrated antiviral effects in Phase 2a clinical trials. However, naturally-occurring polymorphisms proximal to the cleavage site conferred much reduced sensitivity to the effects of bevirimat in vitro which correlated with the clinical response. Guided by assays incorporating the natural polymorphisms, we identified GSK-3532795/BMS-955176 as a second generation HIV-1 maturation inhibitor that exhibits a broader spectrum of antiviral effect in vitro that translated into improved efficacy in clinical trials. In this presentation, we will describe the strategy and tactics adopted by the drug discovery team that led to the discovery of GSK-3532795/BMS-955176, the antiviral and pharmacokinetic profiles of the molecule and the results of early clinical studies.
Nicholas A. Meanwell, Ph.D., FRSC
Nicholas A. Meanwell received his B.Sc. in Special Honors chemistry from the University of Sheffield, Sheffield, England in 1976. In 1979, he earned a Ph.D. degree from the University of Sheffield under the direction of Dr. D. Neville Jones for studies of the application of alkenyl sulfoxides as key intermediates in the synthesis of a series of 9-deoxyprostaglandin and 9-thiaprostaglandin derivatives and the fragrance dihydrojasmone.
From 1979-1982, Dr. Meanwell conducted post-doctoral training under the supervision of Professor Carl R. Johnson at Wayne State University, Detroit, MI, where he devised a general synthetic approach to sulfoximine derivatives via sulfonimidoyl fluorides, completed the synthesis and sulfoximine-mediated resolution of the ginseng constituent β-panasinsene and devised a synthetic approach to a series of cylcopentane-containing natural products including hop ether, cis-jasmone, sarkomycin and known synthetic precursors to 11-deoxy-prostaglandins and PGE2 from a common intermediate.
In 1982, Dr. Meanwell joined Bristol-Myers Squibb where he led teams in the cardiovascular therapeutic area that developed a series of imidazo[4,5-b]quinolin-2-ones as selective phosphodiesterase III inhibitors, potential antithrombotic agents based on blood platelet aggregation inhibition. His team also mapped the non-prostanoid prostacyclin mimetic pharmacophore, defined most effectively by BMY-45778, a potent partial agonist that inhibited blood platelet aggregation induced by a range of activators, and contributed to the design of inhibitors of thrombin.
From 1991 to 1994, Dr. Meanwell contributed to CNS drug discovery efforts, leading the early phase team that explored the potential of Ca2+-dependent potassium channel modulators, a program that ultimately produced the Maxi K ion channel opener flindokalner (MaxiPostTM) which was advanced into Phase III clinical trials for the treatment of stroke. In 1994, Dr. Meanwell assumed responsibility for antiviral drug discovery chemistry with the objective of establishing programs directed toward the discovery and development of inhibitors of human immunodeficiency virus-1 (HIV-1), hepatitis C virus (HCV) and respiratory viruses, including influenza and respiratory syncytial virus (RSV). From this initiative, a series of RSV fusion inhibitors were characterized as the first small molecules to interfere with the association of the 6 helical peptide bundle that is a critical step in the virus entry process, with BMS-433771 nominated as a clinical candidate.
A series of HIV-1 attachment inhibitors, the first small molecules described to function by interfering with the interaction between virus gp120 and the host cell CD4 receptor, were identified and optimized, with several compounds advanced into clinical trials from which BMS-488043 established clinical proof-of-concept for this mechanism. BMS-663068, a phosphonooxymethyl prodrug of BMS-626529, has successfully completed Phase 2 clinical trials and has entered Phase 3 studies.
In the arena of HCV inhibition, key discoveries to emerge from the group include the NS5A inhibitor daclatasvir (DaklinzaTM), a first-in-class molecule that established this protein as a clinically-relevant target, and the HCV NS3 protease inhibitor asunaprevir (SunvepraTM), which incorporates the cyclopropyl acylsulfonamide moiety that has been widely adopted. The combination of daclatasvir and asunaprevir in a clinical trial conducted in HCV-infected subjects who had failed pegylated interferon/ribavirin therapy, established for the first time that an HCV infection could be cured by direct acting antiviral agents in the absence of immune stimulation. The combination of DaklinzaTM and SunvepraTM was approved in Japan in 2014 for the treatment of genotype 1b HCV infection and DaklinzaTM was approved for marketing by the European Medicines Agency in 2014. In addition, beclabuvir, a thumb site inhibitor of HCV NS5B polymerase, has completed Phase 3 trials as a fixed-dose combination therapy with daclatasvir and asunaprevir.
Dr. Meanwell is the author/co-author of over 200 publications, review articles, book chapters and editorials and more than 170 meeting abstracts. He is named as an inventor/co-inventor of more than 110 granted U.S. Patents. Dr. Meanwell has presented over 120 invited lectures at National and International meetings, Universities and Schools on Medicinal Chemistry describing aspects of antiviral drug discovery and development and principles of drug design.
In 2014, Dr. Meanwell was recognized for outstanding research in the area of HIV/AIDS as a co-recipient of a PhRMA Research and Hope Award for Biopharmaceutical Industry Research for the discovery and development of HIV-1 attachment inhibitors. In 2015, Dr. Meanwell received the 2015 Philip S. Portoghese Journal of Medicinal Chemistry/ACS Division of Medicinal Chemistry Joint Lectureship Award. He was named to the American Chemical Society Medicinal Chemistry Hall of Fame in August 2015.