RESUMO
The discovery and optimization of a novel series of GPR142 agonists are described. These led to the identification of compound 21 (LY3325656), which demonstrated anti-diabetic benefits in pre-clinical studies and ADME/PK properties suitable for human dosing. Compound 21 is the first GPR142 agonist molecule advancing to phase 1 clinic trials for the treatment of Type 2 diabetes.
Assuntos
Benzamidas/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Receptores Acoplados a Proteínas G/agonistas , Triazóis/uso terapêutico , Animais , Benzamidas/síntese química , Benzamidas/farmacocinética , Cães , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Técnicas de Inativação de Genes , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacocinética , Camundongos Knockout , Estrutura Molecular , Ratos , Receptores Acoplados a Proteínas G/genética , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/farmacocinéticaRESUMO
A total synthesis of the caribenol A (1), a novel natural product with an intriguing tetracyclic framework, has been achieved. The synthesis features an intramolecular Diels-Alder (IMDA) reaction for the facile construction of the tricyclic [5-7-6] skeleton of caribenol A (1) and a biomimetic oxidation reaction for the formation of the 2-hydroxyfuran-2(5H)-one motif of caribenol A (1) as key steps. This synthetic approach also reveals that the sp(2) carbon at C(2) in substrate 8 is a critical factor for the formation of the tricyclic [5-7-6] skeleton in 7.
Assuntos
Diterpenos/síntese química , Cristalografia por Raios X , Ciclização , Diterpenos/química , Modelos Moleculares , Conformação MolecularRESUMO
A unified strategy toward the asymmetric total synthesis of carbenol A is reported, featuring intramolecular Diels-Alder (IMDA) and biomimetic oxidation reactions as key steps.
Assuntos
Antibacterianos/síntese química , Diterpenos/síntese química , Antibacterianos/química , Cristalografia por Raios X , Diterpenos/química , Modelos Moleculares , Conformação Molecular , EstereoisomerismoRESUMO
Caribenol Queen: A new asymmetric, protecting-group-free synthesis of the marine tetracyclic diterpenoid (+)-caribenol A (1) has been achieved. The enantioselective synthesis employed (S)-methyl 1-methyl-2-oxocyclopent-3-enecarboxylate as a chiral scaffold, and an intramolecular Diels-Alder (IMDA) reaction of substrate 3 afforded the [5.7.6] tricyclic core in compound 2.