ABSTRACT
The preparation of a series of substituted indoles coupled to six- and seven-membered cyclic lactams is described and their role as human glycogen phosphorylase a inhibitors discussed. The SAR of the indole moiety and lactam ring are presented.
Subject(s)
Enzyme Inhibitors/pharmacology , Glycogen Phosphorylase/antagonists & inhibitors , Quinolines/chemical synthesis , Quinolines/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Kinetics , Models, Molecular , Molecular Conformation , Quinolines/chemistry , Structure-Activity RelationshipABSTRACT
A new class of 4-(aminoheterocycle)piperidine derived 1,3,4 trisubstituted pyrrolidine CCR5 antagonists is reported. Compound 4a is shown to have good binding affinity (1.8 nM) and antiviral activity in PBMC's (IC(95)=50 nM). Compound 4a also has improved PK properties relative to 1.
Subject(s)
CCR5 Receptor Antagonists , Piperidines/chemical synthesis , Piperidines/pharmacology , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Animals , Anti-HIV Agents/chemical synthesis , CHO Cells , Chemokine CCL4 , Cricetinae , Half-Life , HeLa Cells , Humans , Hydrogen Bonding , Macrophage Inflammatory Proteins/metabolism , Piperidines/pharmacokinetics , Pyrrolidines/pharmacokinetics , RatsABSTRACT
The 4-(3-phenylprop-1-yl)piperidine moiety of the 1,3,4-trisubstituted pyrrolidine CCR5 antagonist 1 was modified with electron deficient aromatics as well as replacement of the benzylic methylene with sulfones, gem-difluoromethylenes and alcohols in an effort to balance the antiviral potency with reasonable pharmacokinetics.
Subject(s)
Anti-HIV Agents/chemical synthesis , CCR5 Receptor Antagonists , Pyrrolidines/pharmacokinetics , Animals , Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/pharmacology , Dogs , Half-Life , Humans , Leukocytes, Mononuclear , Macaca mulatta , Metabolic Clearance Rate , Piperidines/chemistry , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Radioligand Assay , Rats , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Preparation and screening of mixture libraries based on a 2-arylindole scaffold resulted in the discovery of potent ligands for a variety of G-protein coupled receptors.
