ABSTRACT
The NO-sGC-cGMP signaling pathway plays an important role in the cardiovascular system. Loss of nitric oxide tone or impaired signaling has been associated with cardiovascular diseases, such as hypertension, pulmonary hypertension and heart failure. Direct activation of sGC enzyme independent of NO represents a novel approach for modulating NO signaling with tremendous therapeutic potential. Herein, we describe the design of a structurally novel class of heme-dependent sGC stimulators containing the 3,3-dimethylpyrrolidin-2-one moiety which resulted in the identification of the potent, selective stimulator 30 (MK-2947) for the treatment of hypertension.
Subject(s)
Antihypertensive Agents/pharmacology , Drug Discovery , Hypertension/drug therapy , Soluble Guanylyl Cyclase/metabolism , Antihypertensive Agents/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
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.
