ABSTRACT
A novel series of potent inhibitors of Ras farnesyl transferase possessing a 1,2,4-triazole pharmacophore is described. These inhibitors were discovered from a parallel synthesis effort and were subsequently optimized to in vitro IC(50) value of less than 1nM.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Farnesyltranstransferase/antagonists & inhibitors , Triazoles/chemical synthesis , Amino Acid Sequence , Enzyme Inhibitors/pharmacology , Farnesyltranstransferase/genetics , Genes, ras , Models, Molecular , Molecular Conformation , Oligopeptides/chemistry , Triazoles/pharmacologyABSTRACT
Anti-AIDS drug candidate and non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125-R165335 (etravirine) caused an initial drop in viral load similar to that observed with a five-drug combination in naïve patients and retains potency in patients infected with NNRTI-resistant HIV-1 variants. TMC125-R165335 and related anti-AIDS drug candidates can bind the enzyme RT in multiple conformations and thereby escape the effects of drug-resistance mutations. Structural studies showed that this inhibitor and other diarylpyrimidine (DAPY) analogues can adapt to changes in the NNRTI-binding pocket in several ways: (1). DAPY analogues can bind in at least two conformationally distinct modes; (2). within a given binding mode, torsional flexibility ("wiggling") of DAPY analogues permits access to numerous conformational variants; and (3). the compact design of the DAPY analogues permits significant repositioning and reorientation (translation and rotation) within the pocket ("jiggling"). Such adaptations appear to be critical for potency against wild-type and a wide range of drug-resistant mutant HIV-1 RTs. Exploitation of favorable components of inhibitor conformational flexibility (such as torsional flexibility about strategically located chemical bonds) can be a powerful drug design concept, especially for designing drugs that will be effective against rapidly mutating targets.
Subject(s)
Anti-HIV Agents/chemistry , Drug Resistance, Viral , HIV Reverse Transcriptase/chemistry , Pyridazines/chemistry , Reverse Transcriptase Inhibitors/chemistry , Crystallography, X-Ray , HIV Reverse Transcriptase/genetics , Models, Molecular , Mutation , Nitriles , Protein Conformation , Pyrimidines/chemistryABSTRACT
We have systematically explored the structure-activity relationship (SAR) for a series of compounds 2 as inhibitors of tripeptidyl-peptidase II (TPP II), a serine protease responsible for the degradation of cholecystokinin-8 (CCK-8). This SAR evaluation of the core structure 2 suggest a fairly restrictive pharmacophore for such related structures, but has yielded a limited set of compounds (2b, 2c, 2d, 2s, and 2t) with potent TPP II inhibitory activity (IC(50) 4-11 nM).
Subject(s)
Indoles/chemical synthesis , Indoles/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Serine Endopeptidases/metabolism , Aminopeptidases , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases , Imidazoles/chemistry , Imidazoles/pharmacology , Indoles/chemistry , Kinetics , Models, Molecular , Molecular Structure , Protease Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
Butabindide, 1, was previously reported as a potent inhibitor (IC50 = 7 nM) of the serine protease enzyme tripeptidyl peptidase II (TPPII), an endogenous protease that degrades cholecystokinin-8 (CCK-8). We found that 1 has some inherent chemical instability, yielding diketopiperazine 2 fairly readily under mimicked physiological conditions. We therefore prepared imidazoles 3, which are void of 1's inherent instability, and have found that our novel analogues maintained comparable TPPII inhibitory activity (e.g.,for 3c, IC50 = 4 nM) as 1.
