ABSTRACT
A series of 1,3,4-trisubstituted pyrrolidine CCR5 receptor antagonists containing a variety of fused heterocycles at the 4-position of the piperidine side chain has been discovered, which are orally bioavailable with potent anti-HIV activity.
Subject(s)
Anti-HIV Agents/chemistry , CCR5 Receptor Antagonists , Heterocyclic Compounds/chemistry , Pyrrolidines/chemistry , Administration, Oral , Animals , Anti-HIV Agents/pharmacokinetics , HeLa Cells , Heterocyclic Compounds/pharmacokinetics , Humans , Pyrrolidines/pharmacokinetics , Rats , Receptors, CCR5/metabolismABSTRACT
[reaction: see text] A novel approach to alpha,alpha-disubstituted-beta-amino acids (beta(2,2)-amino acids) was employed in the synthesis of a series of 3-(pyrrolidin-1-yl)propionic acids possessing high affinity for the CCR5 receptor and potent anti-HIV activity. The rat pharmacokinetics for these new analogues featured higher bioavailabilities and lower rates of clearance as compared to cyclopentane 1.
Subject(s)
Anti-HIV Agents/pharmacology , CCR5 Receptor Antagonists , Propionates/pharmacology , Pyrrolidines/pharmacology , Anti-HIV Agents/pharmacokinetics , Biological Availability , Propionates/pharmacokinetics , Pyrrolidines/pharmacokineticsABSTRACT
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
Incorporation of acidic functional groups into a lead CCR5 antagonist identified from a targeted combinatorial library resulted in compounds with enhanced anti-HIV-1 activity and attenuated L-type calcium channel affinity.
Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , CCR5 Receptor Antagonists , HIV-1/drug effects , Animals , Anti-HIV Agents/pharmacokinetics , CHO Cells , Calcium Channels, L-Type/drug effects , Chemical Phenomena , Chemistry, Physical , Chemokine CCL4 , Cricetinae , Half-Life , HeLa Cells , Humans , Macrophage Inflammatory Proteins/antagonists & inhibitors , Rats , Receptors, CCR5/chemistry , Structure-Activity RelationshipABSTRACT
A series of alpha-(pyrrolidin-1-yl)acetic acids is presented as selective and potent antivirals against HIV. Several of the pyrrolidine zwitterions demonstrated reasonable in vitro properties, enhanced antiviral activities and improved pharmacokinetic profiles over pyrrolidine 1.
