ABSTRACT
In a series of bradykinin B1 antagonists, we discovered that replacement of oxopiperazine acetamides with dehydro-oxopiperazine acetamides provided compounds with enhanced activity against the B1 receptor. The synthesis and SAR leading to potent analogs with reduced molecular weight will be discussed.
Subject(s)
Acetamides/pharmacology , Bradykinin B1 Receptor Antagonists , Piperazines/pharmacology , Acetamides/chemical synthesis , Acetamides/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Piperazines/chemical synthesis , Piperazines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The insulin-like growth factor-1 receptor (IGF-1R) plays an important role in the regulation of cell growth and differentiation, and in protection from apoptosis. IGF-1R has been shown to be an appealing target for the treatment of human cancer. Herein, we report the synthesis, structure-activity relationships (SAR), X-ray cocrystal structure and in vivo tumor study results for a series of 2,4-bis-arylamino-1,3-pyrimidines.
Subject(s)
Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Quinolines/chemical synthesis , Receptor, IGF Type 1/antagonists & inhibitors , Animals , Binding Sites , Crystallography, X-Ray , Drug Evaluation, Preclinical , Humans , Mice , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Quinolines/chemistry , Quinolines/pharmacokinetics , Receptor, IGF Type 1/metabolism , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Thiazolones with an exo-norbornylamine at the 2-position and an isopropyl group on the 5-position are potent 11beta-HSD1 inhibitors. However, the C-5 center was prone to epimerization in vitro and in vivo, forming a less potent diastereomer. A methyl group was added to the C-5 position to eliminate epimerization, leading to the discovery of (S)-2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (AMG 221). This compound decreased fed blood glucose and insulin levels and reduced body weight in diet-induced obesity mice.
