RESUMO
Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V(1b) antagonists are described. 2-(6-Aminomethylaryl-2-aryl-4-oxo-quinazolin-3(4H)-yl)acetamide have been identified with low nanomolar affinity for the V(1b) receptor and good selectivity with respect to related receptors V(1a), V(2) and OT. Optimised compound 16 shows a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction.
Assuntos
Acetamidas/síntese química , Antagonistas dos Receptores de Hormônios Antidiuréticos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Quinazolinonas/síntese química , Quinazolinonas/farmacologia , Acetamidas/química , Acetamidas/farmacologia , Animais , Células CACO-2 , Humanos , Concentração Inibidora 50 , Masculino , Estrutura Molecular , Quinazolinonas/química , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V(1b) (V(3)) antagonists are described. 2-(4-Oxo-2-aryl-quinazolin-3(4H)-yl)acetamides have been identified with low nanomolar affinity for the V(1b) receptor and good selectivity with respect to related receptors V(1a), V(2) and oxytocin (OT). Optimised compound 12j demonstrates a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Quinazolinas/síntese química , Quinazolinas/farmacologia , Animais , Humanos , Quinazolinas/química , Quinazolinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Integrina alfaVbeta3/antagonistas & inibidores , Receptores de Vitronectina/antagonistas & inibidores , Disponibilidade Biológica , Linhagem Celular , Humanos , Compostos Macrocíclicos/farmacocinética , Compostos Macrocíclicos/farmacologia , Relação Estrutura-AtividadeRESUMO
A new structural class of triaminotriazine aniline amides possessing potent p38 enzyme activity has been discovered. The initial hit (compound 1a) was identified through screening the Pharmacopeia ECLiPS compound collection. SAR modification led to the identification of a short acting triaminotriazine aniline methoxyamide (compound 1m) possessing in vitro and in vivo oral activity in animal models of acute and chronic inflammatory disease. An X-ray crystal structure of compound 1m in this class, cocrystallized with unactivated p38 alpha protein, indicates that these compounds bind to the ATP binding pocket and possess key H-bonding interactions within a deeper cleft. Hydrogen bonding between one of the triazine nitrogens and the backbone NH of the Met109 residue occurs through a water molecule. The methoxyamide NH and carbonyl oxygen are within H-bonding distance of Glu71 and Asp168.
