ABSTRACT
A novel series of o-phenylenediamine-based inhibitors of indoleamine 2,3-dioxygenase (IDO) has been identified. IDO is a heme-containing enzyme, overexpressed in the tumor microenvironment of many cancers, which can contribute to the suppression of the host immune system. Synthetic modifications to a previously described diarylether series resulted in an additional degree of molecular diversity which was exploited to afford compounds that demonstrated significant potency in the HeLa human cervical cancer IDO1 assay. .
Subject(s)
Enzyme Inhibitors/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Phenylenediamines/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , HeLa Cells , Humans , Microsomes, Liver/metabolism , Phenylenediamines/chemical synthesis , Phenylenediamines/chemistry , Phenylenediamines/metabolism , Structure-Activity RelationshipABSTRACT
This letter describes the discovery, synthesis, SAR, and biological activity of [2.2.1]-bicyclic sultams as potent antagonists of the androgen receptor. Optimization of the series led to the identification of compound 25, which displayed robust pharmacodynamic effects in rats after oral dosing.
Subject(s)
Androgen Receptor Antagonists/chemistry , Androgen Receptor Antagonists/pharmacology , Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/pharmacology , Naphthalenesulfonates/chemistry , Naphthalenesulfonates/pharmacology , Administration, Oral , Androgen Receptor Antagonists/pharmacokinetics , Animals , Bridged Bicyclo Compounds/administration & dosage , Bridged Bicyclo Compounds/pharmacokinetics , Cell Line, Tumor , Humans , Models, Molecular , Naphthalenesulfonates/administration & dosage , Naphthalenesulfonates/pharmacokinetics , Rats , Receptors, Androgen/metabolism , Structure-Activity RelationshipABSTRACT
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
Allyl(crotyl)enolsilanes, when constrained in a five-membered ring with a 1,2-diol, react with aldehydes in a tandem aldol-allylation reaction to give polyketide fragments. These experimentally trivial and efficient reactions establish two new carbon-carbon bonds and up to four new stereocenters. The silane reagents, which owe their reactivity to strain release Lewis acidity, are easily prepared and stable to storage.
