RESUMO
In this manuscript, we report a series of chiral 6-azaspiro[2.5]octanes and related spirocycles as highly potent and selective antagonists of the muscarinic acetylcholine receptor subtype 4 (mAChR4). Chiral separation and subsequent X-ray crystallographic analysis of early generation analogs revealed the R enantiomer to possess excellent human and rat M4 potency, and further structure-activity relationship (SAR) studies on this chiral scaffold led to the discovery of VU6015241 (compound 19). Compound 19 is characterized by high M4 potency and selectivity across multiple species, excellent aqueous solubility, and moderate brain exposure in rodents after intraperitoneal administration.
Assuntos
Antagonistas Muscarínicos/farmacologia , Receptor Muscarínico M4/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Antagonistas Muscarínicos/síntese química , Antagonistas Muscarínicos/química , Receptor Muscarínico M4/metabolismo , Relação Estrutura-AtividadeRESUMO
Herein, we report the SAR leading to the discovery of VU6028418, a potent M4 mAChR antagonist with high subtype-selectivity and attractive DMPK properties in vitro and in vivo across multiple species. VU6028418 was subsequently evaluated as a preclinical candidate for the treatment of dystonia and other movement disorders. During the characterization of VU6028418, a novel use of deuterium incorporation as a means to modulate CYP inhibition was also discovered.
RESUMO
Because of its remarkable potency and relative ease of synthesis, carfentanil (1) has recently emerged as a problematic contaminant in other drugs of abuse. Carfentanil and its close analogues, currently approved only for large animal veterinary medicine, have found use both as illicit additives to the clandestine manufacture of scheduled drugs and as chemical weapons. In this Review, the background, synthesis, manufacture, metabolism, pharmacology, approved indications, dosage, and adverse effects of carfentanil will be discussed along with its emergence as a key player in the ongoing opioid crisis.