ABSTRACT
(2S)-2-(3-Chlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (1b) has been identified as a potent CCR5 antagonist having an IC50=10 nM. Herein, structure-activity relationship studies of non-spiro piperidines are described, which led to the discovery of 4-(N-(alkyl)-N-(benzyloxycarbonyl)amino)piperidine derivatives (3-5) as potent CCR5 antagonists.
Subject(s)
Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Butanes/chemistry , Butanes/chemical synthesis , Butanes/pharmacology , CCR5 Receptor Antagonists , Piperidines/chemistry , Piperidines/pharmacology , Animals , Cells, Cultured , Cricetinae , Drug Design , Drug Evaluation, Preclinical , HIV-1/drug effects , Humans , Inhibitory Concentration 50 , Neutrophils/drug effects , Neutrophils/virology , Structure-Activity RelationshipABSTRACT
Recent results from human clinical trials have established the critical role of HIV protease inhibitors in the treatment of acquired immune-deficiency syndrome (AIDS). However, the emergence of viral resistance, demanding treatment protocols, and adverse side effects have exposed the urgent need for a second generation of HIV protease inhibitors. The continued exploration of our hydroxylaminepentanamide (HAPA) transition-state isostere series of HIV protease inhibitors, which initially resulted in the identification of Crixivan (indinavir sulfate, MK-639, L-735,524), has now yielded MK-944a (L-756,423). This compound is potent, is selective, and competitively inhibits HIV-1 PR with a K(i) value of 0.049 nM. It stops the spread of the HIV(IIIb)-infected MT4 lymphoid cells at 25.0-50.0 nM, even in the presence of alpha(1) acid glycoprotein, human serum albumin, normal human serum, or fetal bovine serum. MK-944a has a longer half-life in several animal models (rats, dogs, and monkeys) than indinavir sulfate and is currently in advanced human clinical trials.
Subject(s)
Antiviral Agents/chemical synthesis , HIV Protease Inhibitors/chemical synthesis , HIV-1/drug effects , Indans/chemical synthesis , Piperazines/chemical synthesis , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Cattle , Cell Culture Techniques , Dogs , Drug Evaluation, Preclinical , Drug Resistance, Microbial , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/pharmacokinetics , HIV Protease Inhibitors/pharmacology , Haplorhini , Humans , Indans/chemistry , Indans/pharmacokinetics , Indans/pharmacology , Male , Piperazines/chemistry , Piperazines/pharmacokinetics , Piperazines/pharmacology , Protein Binding , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Urinary Calculi/chemically induced , Urinary Calculi/urineSubject(s)
Acquired Immunodeficiency Syndrome/drug therapy , Antiviral Agents/pharmacology , Drug Resistance, Microbial , HIV Infections/drug therapy , HIV-1/drug effects , Antiviral Agents/therapeutic use , Drug Design , Drug Resistance, Microbial/genetics , Drug Therapy, Combination , HIV-1/genetics , Humans , Microbial Sensitivity Tests , Point Mutation , Zidovudine/pharmacologyABSTRACT
A series of glycopeptidemimetics based on the hydroxyethylene Phe-Phe isostere have been synthesized and evaluated for their ability to inhibit the enzyme HIV-1 protease. Incorporation of carbohydrate moieties at the P'2-position and elimination of P'3 amino acid in our lead compound 1, provided inhibitors with only nanomolar potencies (400-800 nM). However, incorporation of a carbohydrate moiety at the P'3-position with branched chain amino acid at the P'2-position, resulted in inhibitors with subnanomolar potencies. Within this series, compound 21 was the most potent inhibitor (IC50 value 0.17 nM). This compound has also shown to block the spread of HIV-1 in T-lymphoid cells at an inhibitor concentration of 200 nM.