RESUMO
Systematic SAR optimization of the GPR119 agonist lead 1, derived from an internal HTS campaign, led to compound 29. Compound 29 displays significantly improved in vitro activity and oral exposure, leading to GLP1 elevation in acutely dosed mice and reduced glucose excursion in an OGTT study in rats at doses ⩾10 mg/kg.
Assuntos
Pirimidinas/síntese química , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Animais , Descoberta de Drogas , Camundongos , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
Multiple regions of the 3-oxazolidinedione-6-naphthyl-pyridinone series identified via high throughput screening were explored. SAR studies of these regions including the left-hand side oxazolidinedione moiety, α-substituent on the oxazolidinedione ring, central pyridinone core, and substituents on the central pyridinone core led to the discovery of potent EP(3) receptor antagonists such as compound 29 which possesses outstanding rat pharmacokinetic properties. Synthesis and SAR of these novel compounds and DMPK properties of representative compounds are discussed.
Assuntos
Oxazóis/síntese química , Piridonas/síntese química , Receptores de Prostaglandina E Subtipo EP3/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Estrutura Molecular , Oxazóis/química , Oxazóis/farmacologia , Ligação Proteica/efeitos dos fármacos , Piridonas/química , Piridonas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina E Subtipo EP3/química , Relação Estrutura-AtividadeRESUMO
High-throughput screening and subsequent optimization led to the discovery of novel 3-oxazolidinedione-6-aryl-pyridinones exemplified by compound 2 as potent and selective EP3 antagonists with excellent pharmacokinetic properties. Compound 2 was orally active and showed robust in vivo activities in overactive bladder models. To address potential bioactivation liabilities of compound 2, further optimization resulted in compounds 9 and 10, which maintained excellent potency, selectivity, and pharmacokinetic properties and showed no bioactivation liability in glutathione trapping studies. These highly potent, selective, and orally active EP3 antagonists are excellent tool compounds for investigating and validating potential therapeutic benefits from selectively inhibiting the EP3 receptor.
RESUMO
High-throughput screening of the GSK compound collection against the P2Y(1) receptor identified a novel series of tetrahydro-4-quinolinamine antagonists. Optimal substitution around the piperidine group was pivotal for ensuring activity. An exemplar analog from this series was shown to inhibit platelet aggregation.
