RESUMO
A functional high throughput screen identified a novel chemotype for the positive allosteric modulation (PAM) of the muscarinic acetylcholine receptor (mAChR) subtype 5 (M5). Application of rapid analog, iterative parallel synthesis efficiently optimized M5 potency to arrive at the most potent M5 PAMs prepared to date and provided tool compound 8n (ML380) demonstrating modest CNS penetration (human M5 EC50 = 190 nM, rat M5 EC50 = 610 nM, brain to plasma ratio (Kp) of 0.36).
Assuntos
Sistema Nervoso Central/metabolismo , Descoberta de Drogas , Indazóis/metabolismo , Indazóis/farmacologia , Piperidinas/metabolismo , Piperidinas/farmacologia , Receptor Muscarínico M5/química , Receptor Muscarínico M5/metabolismo , Sulfonamidas/metabolismo , Sulfonamidas/farmacologia , Regulação Alostérica/efeitos dos fármacos , Animais , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala , Humanos , Indazóis/química , Indazóis/farmacocinética , Masculino , Piperidinas/química , Piperidinas/farmacocinética , Ratos , Especificidade por Substrato , Sulfonamidas/química , Sulfonamidas/farmacocinéticaRESUMO
A functional high throughput screen and subsequent multidimensional, iterative parallel synthesis effort identified the first muscarinic acetylcholine receptor (mAChR) negative allosteric modulator (NAM) selective for the M5 subtype. ML375 is a highly selective M5 NAM with submicromolar potency (human M5 IC50 = 300 nM, rat M5 IC50 = 790 nM, M1-M4 IC50 > 30 µM), excellent multispecies PK, high CNS penetration, and enantiospecific inhibition.