ABSTRACT
A novel series of pyridyl carboxamide-based CCR5 inhibitors was designed, synthesized, and demonstrated to be highly potent against HIV-1 infection in both HOS and PBL assays. Attempts to evaluate this series of compounds in a rat PK model revealed its instability in rat plasma. A hypothesis for this liability was proposed, and strategies to overcome this issue were pursued, leading to discovery of highly potent 40 and 41, which featured dramatically improved rat PK profiles.
Subject(s)
Anti-HIV Agents/pharmacokinetics , CCR5 Receptor Antagonists , Carboxylic Acids/pharmacokinetics , Amides/chemistry , Animals , Anti-HIV Agents/blood , Anti-HIV Agents/chemistry , Carboxylic Acids/blood , Carboxylic Acids/chemistry , Drug Discovery , RatsABSTRACT
Based on the original spirodiketopiperazine design framework, further optimization of an orally available CCR5 antagonist was undertaken. Structural hybridization of the hydroxylated analog 4 derived from one of the oxidative metabolites and the new orally available non-hydroxylated benzoic acid analog 5 resulted in another potent orally available CCR5 antagonist 6a as a clinical candidate. Full details of a structure-activity relationship (SAR) study and ADME properties are presented.
Subject(s)
Anti-HIV Agents/chemistry , Benzoates/chemistry , CCR5 Receptor Antagonists , Diketopiperazines/chemistry , Administration, Oral , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacokinetics , Benzoates/chemical synthesis , Benzoates/pharmacokinetics , Diketopiperazines/chemical synthesis , Diketopiperazines/pharmacokinetics , Dogs , Drug Evaluation, Preclinical , Guinea Pigs , Haplorhini , Humans , Rabbits , Rats , Receptors, CCR5/metabolism , Structure-Activity RelationshipABSTRACT
Following the discovery that hydroxylated derivative 3 (Fig. 1) was one of the oxidative metabolites of the original lead 1, it was found that hydroxylated compound 4 possesses higher in vitro anti-HIV potency than the corresponding non-hydroxylated compound 2. Structural hybridation of 4 with the orally available analog 5 resulted in another orally-available spirodiketopiperazine CCR5 antagonist 6a that possesses more favorable pharmaceutical profile for use as a drug candidate.
Subject(s)
Anti-HIV Agents/chemistry , CCR5 Receptor Antagonists , Diketopiperazines/chemistry , Spiro Compounds/chemistry , Administration, Oral , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacokinetics , Cell Line, Tumor , Diketopiperazines/chemical synthesis , Diketopiperazines/pharmacokinetics , Diketopiperazines/pharmacology , Drug Evaluation, Preclinical , HIV Core Protein p24/metabolism , HIV-1/metabolism , Humans , Microsomes, Liver/metabolism , Rats , Receptors, CCR5/metabolism , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , StereoisomerismABSTRACT
Using the previously reported novel spirodiketopiperazine scaffold, the design and synthesis of orally available CCR5 antagonists was undertaken. Compounds possessing a carboxylic acid function in the appropriate position showed improved oral exposure (AUC) relative to the initial chemical leads without reduction in the antagonist activity. The optimized compound 40 was found to show potent anti-HIV activity. Full details of structure-activity relationship (SAR) study are presented.
Subject(s)
Anti-HIV Agents/pharmacology , Anti-HIV Agents/pharmacokinetics , CCR5 Receptor Antagonists , HIV Infections/drug therapy , HIV-1/drug effects , Piperazines/pharmacology , Piperazines/pharmacokinetics , Administration, Oral , Animals , Anti-HIV Agents/chemistry , Biological Availability , Caco-2 Cells , Humans , Piperazines/chemistry , Rats , Receptors, CCR5/metabolismABSTRACT
Spirodiketopiperazine-based CCR5 antagonists, showing improved pharmacokinetic profiles without reduction in antagonist activity, were designed and synthesized. We also demonstrate the anti-HIV activity of a representative compound 12, as measured in a p24 assay.
Subject(s)
Anti-HIV Agents/pharmacokinetics , CCR5 Receptor Antagonists , Piperazines/pharmacokinetics , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , HIV Core Protein p24/metabolism , Humans , Microsomes, Liver/metabolism , Piperazines/chemical synthesis , Piperazines/chemistry , Rats , Receptors, CCR5/metabolismABSTRACT
Hydroxylated derivatives were designed and synthesized based on the information of oxidative metabolites. Compounds derived from beta-substituted (2R,3R)-2-amino-3-hydroxypropionic acid showed improved inhibitory activities against the binding of MIP-1alpha to human CCR5, compared with the non-hydroxylated derivatives and the other isomers.