ABSTRACT
HCV NS5A inhibitors have demonstrated impressive in vitro virologic profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed-dose combination (FDC) regimen for the treatment of HCV infection. Merck's effort in this area identified MK-4882 and MK-8325 as early development leads. Herein, we describe the discovery of potent macrocyclic NS5A inhibitors bearing the MK-8325 or MK-4882 core structure.
Subject(s)
Antiviral Agents/pharmacology , Drug Discovery , Hepacivirus/drug effects , Heterocyclic Compounds, 4 or More Rings/pharmacology , Macrocyclic Compounds/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Dose-Response Relationship, Drug , Hepatitis C/drug therapy , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemistry , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/chemistry , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination treatment regimen. Herein we describe the research efforts that led to the discovery of silyl proline containing HCV NS5A inhibitors such as 7e and 8a with pan-genotype activity profile and acceptable pharmacokinetic properties.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Drug Discovery , Hepacivirus/drug effects , Hepacivirus/genetics , Proline/analogs & derivatives , Silanes/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemical synthesis , Dose-Response Relationship, Drug , Genotype , Microbial Sensitivity Tests , Molecular Structure , Silanes/pharmacology , Structure-Activity Relationship , Viral Nonstructural Proteins/genetics , Virus Replication/drug effectsABSTRACT
BMS-641988 (23) is a novel, nonsteroidal androgen receptor antagonist designed for the treatment of prostate cancer. The compound has high binding affinity for the AR and acts as a functional antagonist in vitro. BMS-641988 is efficacious in multiple human prostate cancer xenograft models, including CWR22-BMSLD1 where it displays superior efficacy relative to bicalutamide. Based on its promising preclinical profile, BMS-641988 was selected for clinical development.
ABSTRACT
A novel series of 4-[3,5-dioxo-11-oxa-4,9-diazatricyclo[5.3.1.0(2,6)]undec-4-yl]-2-trifluoromethyl-benzonitriles has been synthesized. The ability of these compounds to act as antagonists of the androgen receptor was investigated and several were found to have potent activity in vitro and in vivo.
Subject(s)
Antineoplastic Agents/chemical synthesis , Nitriles/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Drug Design , Humans , Male , Nitriles/chemical synthesis , Nitriles/therapeutic use , Prostatic Neoplasms/drug therapy , Receptors, Androgen/metabolism , Structure-Activity RelationshipABSTRACT
Structure-activity relationships in a series of 4-[1H-indazol-5-ylamino]pyrrolo[2,1-f][1,2,4]triazine-6-carbamates identified dual human epidermal growth factor receptor (HER)1/HER2 kinase inhibitors with excellent biochemical potency and kinase selectivity. On the basis of its favorable pharmacokinetic profile and robust in vivo activity in HER1 and HER2 driven tumor models, 13 (BMS-599626) was selected as a clinical candidate for treatment of solid tumors.
Subject(s)
Antineoplastic Agents/chemical synthesis , Carbamates/chemical synthesis , ErbB Receptors/antagonists & inhibitors , Receptor, ErbB-2/antagonists & inhibitors , Triazines/chemical synthesis , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Biological Availability , Carbamates/pharmacokinetics , Carbamates/pharmacology , Cell Line, Tumor , Dogs , Drug Screening Assays, Antitumor , Humans , Macaca fascicularis , Mice , Neoplasm Transplantation , Stereoisomerism , Structure-Activity Relationship , Transplantation, Heterologous , Triazines/pharmacokinetics , Triazines/pharmacologyABSTRACT
Gibbilimbols A-D (1-4) were synthesized in 32-49% yield over four steps from commercially available starting materials. A copper-catalyzed coupling of 4-methoxyphenylmagnesium bromide with various unsaturated alkyl bromides was the key step in assembling the (long-chain alkyl)phenol skeleton.