ABSTRACT
The design and synthesis of potent, tripeptidic acylsulfonamide inhibitors of HCV NS3 protease that contain a difluoromethyl cyclopropyl amino acid at P1 are described. A cocrystal structure of 18 with a NS3/4A protease complex suggests the presence of a H-bond between the polarized C-H of the CHF2 moiety and the backbone carbonyl of Leu135 of the enzyme. Structure-activity relationship studies indicate that this H-bond enhances enzyme inhibitory potency by 13- and 17-fold compared to the CH3 and CF3 analogues, respectively, providing insight into the deployment of this unique amino acid.
ABSTRACT
The synthesis, structure-activity relationship (SAR) data, and further optimization of the metabolic stability and pharmacokinetic (PK) properties for a previously disclosed class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors are described. These efforts led to the discovery of BMS-961955 as a viable contingency backup to beclabuvir which was recently approved in Japan for the treatment of HCV as part of a three drug, single pill combination marketed as XimencyTM.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Benzazepines/chemistry , Benzazepines/pharmacology , Hepacivirus/drug effects , Hepatitis C/drug therapy , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/pharmacokinetics , Benzazepines/pharmacokinetics , Dogs , Haplorhini , Hepacivirus/enzymology , Hepacivirus/metabolism , Hepatitis C/virology , Humans , RNA-Dependent RNA Polymerase/antagonists & inhibitors , RNA-Dependent RNA Polymerase/metabolism , Rats , Viral Nonstructural Proteins/metabolismABSTRACT
The discovery of asunaprevir (BMS-650032, 24) is described. This tripeptidic acylsulfonamide inhibitor of the NS3/4A enzyme is currently in phase III clinical trials for the treatment of hepatitis C virus infection. The discovery of 24 was enabled by employing an isolated rabbit heart model to screen for the cardiovascular (CV) liabilities (changes to HR and SNRT) that were responsible for the discontinuation of an earlier lead from this chemical series, BMS-605339 (1), from clinical trials. The structure-activity relationships (SARs) developed with respect to CV effects established that small structural changes to the P2* subsite of the molecule had a significant impact on the CV profile of a given compound. The antiviral activity, preclincial PK profile, and toxicology studies in rat and dog supported clinical development of BMS-650032 (24).
Subject(s)
Antiviral Agents/therapeutic use , Hepatitis C/drug therapy , Isoquinolines/therapeutic use , Protease Inhibitors/therapeutic use , Sulfonamides/therapeutic use , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/blood , Antiviral Agents/chemistry , Dogs , Humans , Isoquinolines/blood , Isoquinolines/chemistry , Models, Molecular , Protease Inhibitors/blood , Protease Inhibitors/chemistry , Rabbits , Rats , Sulfonamides/blood , Sulfonamides/chemistryABSTRACT
In an era of increasing resistance to classical antibacterial agents, the synthetic oxazolidinone series of antibiotics has attracted much interest. Zyvoxtrade mark was the first oxazolidinone to be approved for clinical use against infections caused by multi-drug resistant Gram-positive bacteria. In the course of studies directed toward the discovery of novel antibacterial agents, a new series of synthetic phenyl-isoxazolinone agents that displayed potent activity against Gram-positive bacterial strains was recently discovered at Bristol-Myers Squibb. Extensive investigation of various substitutions on the phenyl ring was then undertaken. We report here, the synthesis and antibacterial activity of a series of biaryl isoxazolinone compounds.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Isoxazoles/chemistry , Isoxazoles/pharmacology , Animals , Haemophilus influenzae/drug effects , Rats , Structure-Activity RelationshipABSTRACT
This article summarizes key aspects of progress made during 2004 toward the design, discovery and development of antiviral agents for clinical use. Important developments in the identification, characterization and clinical utility of inhibitors of human immunodeficiency virus; the hepatitis viruses, hepatitis B, hepatitis C; the herpes family of viruses, herpes simplex viruses 1 and 2, varicella zoster virus, Epstein-Barr virus and human cytomegalovirus; the respiratory viruses, influenza, respiratory syncytial virus, human metapneumovirus, picornaviruses, measles and the severe acute respiratory syndrome coronavirus; human papilloma virus; rotavirus; Ebola virus and West Nile virus, are reviewed.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Drug Design , HIV-1/drug effects , HIV-2/drug effects , Hepatitis Viruses/drug effects , Herpesviridae/drug effects , Amino Acid Sequence , Animals , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Clinical Trials as Topic , Drug Evaluation, Preclinical , HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , Humans , Molecular Sequence Data , Molecular Structure , Nucleic Acid Synthesis Inhibitors , Nucleosides/chemistry , Nucleosides/pharmacology , Orthomyxoviridae/drug effects , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Severe acute respiratory syndrome-related coronavirus/drug effectsABSTRACT
A series of potential antimicrobial derivatives possessing bioisosteric replacements for the central oxazolidinone ring found in oxazolidinone antibacterials have been prepared. The design concept involved replacement of the requisite sp(3)-hybridized stereogenic center found at the 5-position of the oxazolidinone with a nitrogen atom. The synthesis and antibacterial activity of three such ring systems, the benzisoxazolinones, pyrroles, and isoxazolinones is described.
