RESUMO
Several strategies have been employed to reduce the long in vivo half-life of our lead CB1 antagonist, triazolopyridazinone 3, to differentiate the pharmacokinetic profile versus the lead clinical compounds. An in vitro and in vivo clearance data set revealed a lack of correlation; however, when compounds with <5% free fraction were excluded, a more predictable correlation was observed. Compounds with log P between 3 and 4 were likely to have significant free fraction, so we designed compounds in this range to give more predictable clearance values. This strategy produced compounds with desirable in vivo half-lives, ultimately leading to the discovery of compound 46. The progression of compound 46 was halted due to the contemporaneous marketing and clinical withdrawal of other centrally acting CB1 antagonists; however, the design strategy successfully delivered a potent CB1 antagonist with the desired pharmacokinetic properties and a clean off-target profile.
Assuntos
Piridazinas/farmacocinética , Receptor CB1 de Canabinoide/antagonistas & inibidores , Triazóis/farmacocinética , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Descoberta de Drogas , Meia-Vida , Ligação Proteica , Piridazinas/química , Ratos , Relação Estrutura-Atividade , Triazóis/químicaRESUMO
We have developed a solid phase synthesis route to 1,5-substituted pyrazole-4-carboxamides with three diversity points aimed at the discovery of new compounds as potential G-Protein coupled receptor (GPCR) ligands. The new chemistry involves acylation of a resin bound secondary amine with a ß-ketoester via transamidation, conversion of the resulting ß-ketoamide to the corresponding vinylogous amide, pyrazole formation upon reaction with a aryl hydrzine, and cleavage of the product from the resin. Using the reported methodology, we describe the syntheses of multiple arrays of pyrazoles that were used collectively to construct a library of more than 1000 analogues. Several members of this library displayed submicromolar antagonist activities at the cannabinoid subtype 1 (CB-1) receptor.
Assuntos
Amidas/química , Descoberta de Drogas , Pirazóis/química , Receptor CB1 de Canabinoide/antagonistas & inibidores , Amidas/farmacologia , Concentração Inibidora 50 , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/química , Técnicas de Síntese em Fase SólidaRESUMO
Structure-activity relationships for a series of pyrazine carboxamide CB1 antagonists are reported. Pharmaceutical properties of the series are improved via inclusion of hydroxyl-containing sidechains. This structural modification sufficiently improved ADME properties of an orally inactive series such that food intake reduction was achieved in rat feeding models. Compound 35 elicits a 46% reduction in food intake in ad libidum fed rats 4-h post-dose.