RESUMO
Attempts to block metabolism by incorporating a 9-fluoro substituent at the A-ring of compound 1 (SCH 900229) using electrophilic Selectfluor™ led to an unexpected oxidation of the A-ring to give difluoroquinone analog 1a. Oxidation of other related chromene γ-secretase inhibitors 2-8 resulted in similar difluoroquinone analogs 2a-8a, respectively. These quinone products exhibited comparable in vitro potency in a γ-scretase membrane assay, but were several fold less potent in a cell-based assay in lowering Aß40-42, compared to their parent compounds.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Benzopiranos/química , Inibidores Enzimáticos/química , Sulfonas/química , Benzopiranos/síntese química , Benzopiranos/farmacologia , Benzoquinonas/síntese química , Benzoquinonas/química , Benzoquinonas/farmacologia , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Flúor/química , Flúor/farmacologia , Humanos , Estrutura Molecular , Oxirredução , Sulfonas/síntese química , Sulfonas/farmacologiaRESUMO
Isosteric replacement of the urea group of lead compound 1 led to novel substituted piperidine phenylamide analogues. SAR on the electron-induced effects of various linkers as well as substituents on the phenyl rings and the piperidine nitrogen has been investigated. Many single-digit nanomolar MCH R1 antagonists have been identified from this series.
Assuntos
Piperidinas/síntese química , Piperidinas/farmacologia , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Humanos , 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 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.
