RESUMO
A scaffold hopping strategy was successfully applied in discovering 2-aminooxazole amides as potent DGAT1 inhibitors for the treatment of dyslipidemia. Further optimization in potency and PK properties resulted in a lead series with oral in vivo efficacy in a mouse postprandial triglyceridemia (PPTG) assay.
Assuntos
Amidas/farmacologia , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Oxazóis/farmacologia , Triglicerídeos/sangue , Animais , Humanos , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Biaryl urea lead compound 1 was discovered earlier in our MCH antagonist program. Novel benzimidazole analogues with increased chemical stability, devoid of the potential carcinogenic liability associated with a biarylamine moiety, were synthesized and evaluated to be potent MCH R1 antagonists. Two compounds in this series have demonstrated in vivo efficacy in a rodent obesity model.
Assuntos
Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Peso Corporal/efeitos dos fármacos , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Administração Oral , Animais , Modelos Animais de Doenças , Desenho de Fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
A series of aminoalkylazetidines has been discovered as novel ORL1 receptor ligands. Structure-activity relationships have been investigated at the azetidine N and the alkyl side chain sites. Several potent and selective analogues have been identified.
Assuntos
Azetidinas/síntese química , Azetidinas/farmacologia , Receptores Opioides/efeitos dos fármacos , Animais , Ligação Competitiva/efeitos dos fármacos , Células CHO , Cricetinae , Diprenorfina/farmacologia , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Indicadores e Reagentes , Ligantes , Antagonistas de Entorpecentes/farmacologia , Peptídeos Opioides/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Receptor de Nociceptina , NociceptinaRESUMO
The molecular mechanisms of cholesterol absorption in the intestine are poorly understood. With the goal of defining candidate genes involved in these processes a fluorescence-activated cell sorter-based, retroviral-mediated expression cloning strategy has been devised. SCH354909, a fluorescent derivative of ezetimibe, a compound which blocks intestinal cholesterol absorption but whose mechanism of action is unknown, was synthesized and shown to block intestinal cholesterol absorption in rats. Pools of cDNAs prepared from rat intestinal cells enriched in enterocytes were introduced into BW5147 cells and screened for SCH354909 binding. Several independent clones were isolated and all found to encode the scavenger receptor class B, type I (SR-BI), a protein suggested by others to play a role in cholesterol absorption. SCH354909 bound to Chinese hamster ovary (CHO) cells expressing SR-BI in specific and saturable fashion and with high affinity (K(d) approximately 18 nM). Overexpression of SR-BI in CHO cells resulted in increased cholesterol uptake that was blocked by micromolar concentrations of ezetimibe. Analysis of rat intestinal sections by in situ hybridization demonstrated that SR-BI expression was restricted to enterocytes. Cholesterol absorption was determined in SR-B1 knockout mice using both an acute, 2-h, assay and a more chronic fecal dual isotope ratio method. The level of intestinal cholesterol uptake and absorption was similar to that seen in wild-type mice. When assayed in the SR-B1 knockout mice, the dose of ezetimibe required to inhibit hepatic cholesterol accumulation induced by a cholesterol-containing 'western' diet was similar to wild-type mice. Thus, the binding of ezetimibe to cells expressing SR-B1 and the functional blockade of SR-B1-mediated cholesterol absorption in vitro suggest that SR-B1 plays a role in intestinal cholesterol metabolism and the inhibitory activity of ezetimibe. In contrast studies with SR-B1 knockout mice suggest that SR-B1 is not essential for intestinal cholesterol absorption or the activity of ezetimibe.
Assuntos
Antígenos CD36/metabolismo , Colesterol/metabolismo , Mucosa Intestinal/metabolismo , Proteínas de Membrana , Receptores Imunológicos , Receptores de Lipoproteínas , Animais , Anticolesterolemiantes/farmacologia , Azetidinas/farmacologia , Antígenos CD36/biossíntese , Antígenos CD36/genética , Células CHO , Colesterol/sangue , Clonagem Molecular , Cricetinae , Relação Dose-Resposta a Droga , Ezetimiba , Citometria de Fluxo , Biblioteca Gênica , Hibridização In Situ , Absorção Intestinal/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout , Microscopia de Fluorescência , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Depuradores , Receptores Depuradores Classe BRESUMO
The discoveries of Sch 48461 and Sch 58235 and their novel pharmacology of inhibition of cholesterol absorption have prompted efforts to determine their biological mechanism of action (MOA). To this end, a series of radioiodinated analogues with good to excellent in vivo activity have been designed and synthesized as single enantiomers. They are structurally consistent with the allowable SAR of the 2-azetidinone class of cholesterol absorption inhibitors.
Assuntos
Anticolesterolemiantes/síntese química , Anticolesterolemiantes/farmacologia , Azetidinas/síntese química , Azetidinas/farmacologia , Colesterol/farmacocinética , Absorção Intestinal/efeitos dos fármacos , Animais , Azetidinas/química , Cricetinae , Desenho de Fármacos , Ezetimiba , Marcação por Isótopo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Fluorescent analogues of the cholesterol absorption inhibitor (CAI), Sch 58235, have been designed and synthesized as single enantiomers. Biological testing reveals that they are potent CAIs and are suitable tools for the investigation of the azetidinone CAI mechanism of action (MOA).