RESUMO
DGAT-1 is an enzyme that catalyzes the final step in triglyceride synthesis. mRNA knockout experiments in rodent models suggest that inhibitors of this enzyme could be of value in the treatment of obesity and type II diabetes. The carboxylic acid-based DGAT-1 inhibitor 1 was advanced to clinical trials for the treatment of type 2 diabetes, despite of the low passive permeability of 1. Because of questions relating to the potential attenuation of distribution and efficacy of a poorly permeable agent, efforts were initiated to identify compounds with improved permeability. Replacement of the acid moiety in 1 with an oxadiazole led to the discovery of 52, which possesses substantially improved passive permeability. The resulting pharmacodynamic profile of this neutral DGAT-1 inhibitor was found to be similar to 1 at comparable plasma exposures.
Assuntos
Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Inibidores Enzimáticos/química , Oxazepinas/química , Administração Oral , Animais , Diacilglicerol O-Aciltransferase/metabolismo , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Meia-Vida , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/tratamento farmacológico , Oxidiazóis/química , Oxazepinas/farmacocinética , Oxazepinas/uso terapêutico , Ligação Proteica , Ratos , Relação Estrutura-AtividadeRESUMO
The first highly potent and selective PDE8 inhibitors are disclosed. The initial tetrahydroisoquinoline hit was transformed into a nipecotic amide series in order to address a reactive metabolite issue. Reduction of lipophilicity to address metabolic liabilities uncovered an interesting diastereomer-dependent trend in turnover by human microsomes.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacologia , Inibidores Enzimáticos/farmacologia , Microssomos/efeitos dos fármacos , Ácidos Nipecóticos/química , Amidas/química , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Ligantes , Modelos Moleculares , Estrutura MolecularRESUMO
A series of GPR119 agonists based on a 2,6-diazatricyclo[3.3.1.1â¼3,7â¼]decane ring system is described. Also provided is a detailed account of the development of a multigram scale synthesis of the diazatricyclic ring system, which was achieved using a Hofmann-Löffler-Freytag reaction as the key step. The basis for the use of this complex framework lies in an attempt to constrain one end of the molecule in the "agonist conformation" as was previously described for 3-oxa-7-aza-bicyclo[3.3.1]nonanes. Optimization of carbamate analogues of the diazatricylic compounds led to the identification of 32i as a potent agonist of the GPR119 receptor with low unbound human liver microsomal clearance. The use of an agonist response weighted ligand lipophilic efficiency (LLE) termed AgLLE is discussed along with the issues of applying efficiency measures to agonist programs. Ultimately, solubility limited absorption and poor exposure reduced further interest in these molecules.