RESUMO
Herein we describe a series of tetrahydrobenzotriazoles as novel, potent metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of the SAR surrounding the tetrahydrobenzotriazole core ultimately led to the identification of 29 as a potent mGlu5 PAM with a low maximal glutamate potency fold shift, acceptable in vitro DMPK parameters and in vivo PK profile and efficacy in the rat novel object recognition (NOR) assay. As a result 29 was identified as a suitable compound for progression to in vivo safety evaluation.
Assuntos
Antipsicóticos/química , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Triazóis/química , Regulação Alostérica/efeitos dos fármacos , Animais , Antipsicóticos/metabolismo , Antipsicóticos/farmacologia , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Microssomos/metabolismo , Ratos , Receptor de Glutamato Metabotrópico 5/metabolismo , Relação Estrutura-Atividade , Triazóis/metabolismo , Triazóis/farmacologiaRESUMO
The identification of a highly selective D(2) partial agonist, D(3) antagonist tool molecule which demonstrates high levels of brain exposure and selectivity against an extensive range of dopamine, serotonin, adrenergic, histamine, and muscarinic receptors is described.
Assuntos
Encéfalo/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/antagonistas & inibidores , Animais , Encéfalo/metabolismoRESUMO
[reaction: see text] Aryl epoxyazides undergo efficient electron-deficient reaction cascades mediated by Lewis acids, leading to regiospecific amination of the aromatic ring.
Assuntos
Derivados de Benzeno/química , Carboidratos/síntese química , Manose/química , Derivados de Benzeno/síntese química , Carboidratos/química , Cristalografia por Raios X , Cicloexanonas/química , Cicloexenos/química , Hidrocarbonetos Aromáticos/química , Estrutura Molecular , Oxazóis/química , EstereoisomerismoRESUMO
A rational structure-activity relationship study around compound (1) is reported. The lead optimisation programme led to the identification of sulfonamide (25), a molecule combining dopamine D2/D3 receptor antagonism with serotonin 5-HT2A, 5-HT2C, 5-HT6 receptor antagonism for an effective treatment of schizophrenia. Compound (25) was shown to possess the required in vivo activity with no EPS liability.