ABSTRACT
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
Through the use of computational modeling, a series of pyrimidinetrione-based inhibitors of MMP-13 was designed based on a lead inhibitor identified through file screening. Incorporation of a biaryl ether moiety at the C-5 position of the pyrimidinetrione ring resulted in a dramatic enhancement of MMP-13 potency. Protein crystallography revealed that this moiety binds in the S(1)(') pocket of the enzyme. Optimization of the C-4 substituent of the terminal aromatic ring led to incorporation of selectivity versus MMP-14 (MT-1 MMP). Structure activity relationships of the biaryl ether substituent are presented as is pharmacokinetic data for a compound that meets our in vitro potency and selectivity goals.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Matrix Metalloproteinase Inhibitors , Pyrimidines/chemistry , Binding Sites , Collagenases/chemistry , Crystallography, X-Ray , Enzyme Inhibitors/pharmacology , Matrix Metalloproteinase 13 , Structure-Activity RelationshipABSTRACT
This study evaluated the effectiveness of a self-hypnosis protocol with chronic drug and alcohol patients in increasing self-esteem, improving affect, and preventing relapse against a control, a transtheoretical cognitive-behavioral (TCB), and a stress management (attention-placebo) group. Participants were 261 veterans admitted to Substance Abuse Residential Rehabilitation Treatment Programs (SARRTPs). Participants were assessed pre- and postintervention, and at 7-week follow-up. Relapse rates did not significantly differ across the 4 groups at follow-up; 87% of those contacted reported abstinence. At follow-up, the participants in the 3 treatment conditions were asked how often they practiced the intervention materials provided them. Practicing and minimal-practicing participants were compared against the control group for each of the 3 interventions via MANOVAs/ANOVAs. Results revealed a significant Time by Groups interaction for the hypnosis intervention, with individuals who played the self-hypnosis audiotapes "at least 3 to 5 times a week" at 7-week follow-up reporting the highest levels of self-esteem and serenity, and the least anger/impulsivity, in comparison to the minimal-practice and control groups. No significant effects were found for the transtheoretical or stress management interventions. Regression analyses predicted almost two-thirds of the variance of who relapsed and who did not in the hypnosis intervention group. Hypnotic susceptibility predicted who practiced the self-hypnosis audiotapes. The results suggest that hypnosis can be a useful adjunct in helping chronic substance abuse individuals with their reported self-esteem, serenity, and anger/impulsivity.
Subject(s)
Affect , Hypnosis , Self Concept , Self Efficacy , Substance-Related Disorders/therapy , Adult , Alcoholism/therapy , Chronic Disease , Female , Humans , Male , Middle Aged , Secondary Prevention , Surveys and QuestionnairesABSTRACT
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.
