ABSTRACT
Systematic optimisation of a poorly soluble lead series of isoxazole-3-carboxamides was conducted. Substitution of the 4-position with specific polar functionality afforded the requisite balance of potency, solubility and physicochemical properties. Compound 21a was found to be efficacious in the rat Capsaicin Hargreaves assay following oral administration.
Subject(s)
Cyclohexanols/chemistry , Isoxazoles/chemistry , TRPV Cation Channels/antagonists & inhibitors , Administration, Oral , Amides/chemistry , Amides/pharmacokinetics , Amides/therapeutic use , Animals , Capsaicin/toxicity , Cyclohexanols/pharmacokinetics , Cyclohexanols/therapeutic use , Disease Models, Animal , Drug Evaluation, Preclinical , Humans , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Isoxazoles/pharmacokinetics , Isoxazoles/therapeutic use , Microsomes, Liver/metabolism , Rats , Structure-Activity Relationship , TRPV Cation Channels/metabolismABSTRACT
Optimisation of a screening hit incorporating both TRPV1 activity and solubility was conducted. Substitution of the isoxazole-3-carboxamide with the bespoke 1S, 3R-3-aminocyclohexanol motif afforded the requisite balance of potency and solubility. Compounds 32 and 40 were found to have antihyperalgesic effects in the rat CFA Hg assay and induce a mechanism based hyperthermia.
Subject(s)
Amides/chemistry , Antihypertensive Agents/chemistry , Cyclohexanols/chemistry , Isoxazoles/chemistry , TRPV Cation Channels/antagonists & inhibitors , Amides/chemical synthesis , Amides/pharmacokinetics , Animals , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/pharmacokinetics , Cyclohexanols/chemical synthesis , Cyclohexanols/pharmacokinetics , Hyperthermia, Induced , Isoxazoles/chemical synthesis , Isoxazoles/pharmacokinetics , Rats , Rats, Wistar , Structure-Activity Relationship , TRPV Cation Channels/metabolismABSTRACT
The profile of a series of triazine and pyrimidine based ROCK inhibitors is described. An initial binding mode was established based on a homology model and the proposed interactions are consistent with the observed SAR. Compounds from the series are potent in a cell migration assay and possess a favorable kinase selectivity. In vivo activity was demonstrated for compound 1A in a spontaneous hypertensive rat model.
Subject(s)
Antihypertensive Agents/chemistry , Hypertension/drug therapy , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Triazines/chemistry , rho-Associated Kinases/antagonists & inhibitors , Animals , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/pharmacology , Binding Sites , Computer Simulation , Disease Models, Animal , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Rats , Structure-Activity Relationship , Triazines/chemical synthesis , Triazines/pharmacology , rho-Associated Kinases/metabolismABSTRACT
The discovery, synthesis and preliminary SAR of a novel class of non-peptidic antagonists of the alpha(v)-integrins alpha(v)beta(3) and alpha(v)beta(5) is described. High-throughput screening of an extensive series of ECLiPStrade mark compound libraries led to the identification of compound 1 as a dual inhibitor of the alpha(v)-integrins alpha(v)beta(3) and alpha(v)beta(5). Optimization of compound 1 involving, in part, introduction of two novel constraints led to the discovery of compounds 15a and 15b with reduced PSA and much improved potency for both the alpha(v)beta(3) and alpha(v)beta(5) integrins. Compounds 15a and 15b were shown to have promising activity in functional cellular assays and compound 15a also exhibited a promising Caco-2 permeability profile.
Subject(s)
Integrin alphaVbeta3/antagonists & inhibitors , Receptors, Vitronectin/antagonists & inhibitors , Biological Availability , Cell Line , Humans , Macrocyclic Compounds/pharmacokinetics , Macrocyclic Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
An imidazolylpyrimidine was identified in a CXCR2 chemokine receptor antagonist screen and was optimized for potency, in vitro metabolic stability, and oral bioavailability. It was found that subtle structural modification within the series affected the oral bioavailability. Potent and orally available CXCR2 antagonists are herein reported.
