RESUMO
Acid pump antagonists (APAs) such as the imidazo[1,2-a]pyridine AZD-0865 2 have proven efficacious at low oral doses in acid related gastric disorders. Herein we describe some of the broader SAR in this class of molecule and detail the discovery of an imidazo[1,2-a]pyridine 15 which has excellent efficacy in animal models of gastric acid secretion following oral administration, as well as a good overall developability profile. The discovery strategy focuses on use of heteroaryl and heterocyclic substituents at the C-6 position and optimization of developability characteristics through modulation of global physico-chemical properties.
Assuntos
Inibidores da Bomba de Prótons , Inibidores da Bomba de Prótons/química , Piridinas/química , Administração Oral , Animais , Cães , ATPase Trocadora de Hidrogênio-Potássio/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Inibidores da Bomba de Prótons/síntese química , Inibidores da Bomba de Prótons/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
A new family of cyclometalated (N-heterocyclic carbene)-Pt(II) complexes bearing monodentate phosphines as ancillary ligands has been designed for use as precatalysts in 1,6-enyne cycloisomerization reactions. Highly enantioselective skeletal rearrangements of allylpropargyl-tosylamide derivatives have been developed by using (S)-Ph-Binepine as the chiral auxiliary. Enantiomeric excesses up to 97% have been obtained.