ABSTRACT
To identify chemically and metabolically stable subtype-selective EP4 agonists, design and synthesis of a series of modified γ-lactam prostanoids has been continued. Prostanoids bearing 2-oxo-1,3-oxazolidine, 2-oxo-1,3-thiazolidine and 5-thioxopyrrolidine as a surrogate for the γ-hydroxycyclopentanone without a troublesome 11-hydroxy group were identified as highly subtype-selective EP4 agonists. Among the tested, several representative compounds demonstrated in vivo efficacy after oral dosing in rats. Their pharmacokinetic and structure-activity relationship studies are presented.
Subject(s)
Lactams/chemistry , Prostaglandins/chemistry , Receptors, Prostaglandin E, EP4 Subtype/agonists , Administration, Oral , Animals , Prostaglandins/chemical synthesis , Prostaglandins/pharmacokinetics , Rats , Receptors, Prostaglandin E, EP4 Subtype/metabolism , Structure-Activity Relationship , Thiazolidines/chemistry , Tumor Necrosis Factor-alpha/bloodABSTRACT
To identify structurally novel CRF1 receptor antagonists, a series of bicyclic core antagonists, pyrazolo[1,5-a]pyrimidines, triazolo[1,5-a]pyrimidines, imidazo[1,2-a]pyrimidines and pyrazolo[1,5-a][1,3,5]triazines were designed, synthesized and evaluated as CRF1 receptor antagonists. Compounds 2-27 showed binding affinity (IC(50)=4.2-418 nM) and antagonist activity (EC(50)=4.0-889 nM). Compound 5 was found to show oral efficacy in an Elevated Plus Maze test in rats. Further chemical modification of them led us to discovery of the tricyclic core antagonists pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidines. The discovery process of these compounds is presented, as is the study of the structure-activity relationship.
Subject(s)
Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Receptors, Corticotropin-Releasing Hormone/chemistry , Animals , Humans , Kinetics , Male , Protein Binding , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
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
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.
