ABSTRACT
The biochemical basis for S9-dependent mutagenic response of the 5-HT(2C) receptor agonist and diazinylpiperazine derivative 1 in the Salmonella Ames assay involves P450-mediated bioactivation to DNA-reactive quinone-methide, aldehyde and nitrone intermediates. Mechanistic information pertaining to the metabolism of 1 was used in the design of diazinylpiperazine 5 to eliminate the safety liability. While 5 was negative in the Ames assay, the compound retained the ability of 1 to form certain electrophilic intermediates. Plausible hypotheses that can collectively account for the differences in mutagenic response of the two piperazine analogs are discussed.
Subject(s)
Chemistry, Pharmaceutical/methods , Piperazines/chemistry , Serotonin 5-HT2 Receptor Agonists , Amides/chemistry , Chromatography/methods , Drug Design , Models, Chemical , Mutagenesis , Mutagenicity Tests , Mutagens , Mutation , NADP/chemistry , Piperazine , Reproducibility of Results , Salmonella/metabolismABSTRACT
The synthesis, structure-activity relationship, in vivo activity, and metabolic profile for a series of triazolopyridine-oxazole based p38 inhibitors are described. The deficiencies of the lead structure in the series, CP-808844, were overcome by changes to the C4 aryl group and the triazole side-chain culminating in the identification of several potential clinical candidates.
Subject(s)
Enzyme Inhibitors/pharmacology , Oxazoles/chemistry , Pyridines/chemistry , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/chemistry , Chemistry, Pharmaceutical , Drug Design , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Kinetics , Models, Chemical , Solubility , Structure-Activity Relationship , Triazoles/chemistryABSTRACT
Mimics of the benzimidazolone nucleus found in inhibitors of p38 kinase are proposed, and their theoretical potential as bioisosteres is described. A set of calculated descriptors relevant to the anticipated binding interaction for the fragments 1-methyl-1H-benzotriazole 5, 3-methyl-benzo[d]isoxazole 3, and 3-methyl-[1,2,4]triazolo[4,3-a]pyridine 4, pyridine 1, and 1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one 2 are reported. The design considerations and synthesis of p38 inhibitors based on these H-bond acceptor fragments is detailed. Comparative evaluation of the pyridine-, benzimidazolone-, benzotriazole-, and triazolopyridine-based inhibitors shows the triazoles 20 and 25 to be significantly more potent experimentally than the benzimidazolone after which they were modeled. An X-ray crystal structure of 25 bound to the active site shows that the triazole group serves as the H-bond acceptor but unexpectedly as a dual acceptor, inducing movement of the crossover connection of p38alpha. The computed descriptors for the hydrophobic and pi-pi interaction capacities were the most useful in ranking potency.
Subject(s)
Benzimidazoles/chemistry , Pyridines/chemistry , Triazoles/chemistry , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/chemistry , Benzimidazoles/chemical synthesis , Binding Sites , Crystallography, X-Ray , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Models, Molecular , Molecular Mimicry , Molecular Structure , Protein Binding , Pyridines/chemical synthesis , Quantitative Structure-Activity Relationship , Static Electricity , Triazoles/chemical synthesisABSTRACT
The SAR of a series of sterically hindered sulfonamide hydroxamic acids with relatively large P1' groups is described. The compounds typically spare MMP-1 while being potent inhibitors of MMP-13. The metabolically more stable compounds in the series contain either a monocyclic or bicyclic pyran ring adjacent to the hydroxamate group. Despite the sparing of MMP-1, pre-clinical and clinical studies revealed that fibrosis in rats and MSS in humans is still produced.
Subject(s)
Matrix Metalloproteinase 1/metabolism , Matrix Metalloproteinase Inhibitors , Protease Inhibitors/chemical synthesis , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Hydroxamic Acids/chemistry , Matrix Metalloproteinase 13 , Matrix Metalloproteinases/metabolism , Protease Inhibitors/pharmacology , Pyrans/chemistry , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
The synthesis and in vitro p38 alpha activity of a novel series of benzimidazolone inhibitors is described. The p38 alpha SAR is consistent with a mode of binding wherein the benzimidazolone carbonyl serves as the H-bond acceptor to Met109 of p38 alpha in a manner analogous to the pyridine nitrogen of prototypical pyridylimidazole p38 inhibitors. Potent p38 alpha activity comparable to that of several previously reported p38 inhibitors is observed for this novel chemotype.
