RESUMO
Herein, we report the discovery of the first selective and CNS penetrant mGlu7 PAM (VU6027459) derived from a "molecular switch" within a selective mGlu7 NAM chemotype. VU6027459 displayed CNS penetration in both mice (Kp = 2.74) and rats (Kp= 4.78), it was orally bioavailable in rats (%F = 69.5), and undesired activity at DAT was ablated.
RESUMO
This letter describes a diversity-oriented library approach to rapidly assess diverse heterocycles as bioisosteric replacements for a metabolically labile amide moiety within a series of mGlu7 negative allosteric modulators (NAMs). SAR rapidly honed in on either a 1,2,4- or 1,3,4-oxadizaole ring system as an effective bioisostere for the amide. Further optimization of the southern region of the mGlu7 NAM chemotype led to the discovery of VU6019278, a potent mGlu7 NAM (IC50â¯=â¯501â¯nM, 6.3% L-AP4 Min) with favorable plasma protein binding (rat fuâ¯=â¯0.10), low predicted hepatic clearance (rat CLhepâ¯=â¯27.7â¯mL/min/kg) and high CNS penetration (rat Kpâ¯=â¯4.9, Kp,uuâ¯=â¯0.65).
Assuntos
Amidas/química , Compostos Heterocíclicos/química , Receptores de Glutamato Metabotrópico/química , Regulação Alostérica , Animais , Sistema Nervoso Central/metabolismo , Hepatócitos/citologia , Hepatócitos/metabolismo , Compostos Heterocíclicos/metabolismo , Concentração Inibidora 50 , Pirazóis/química , Pirazóis/metabolismo , Ratos , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-AtividadeRESUMO
Herein, we report the discovery of a new, orally bioavailable and CNS-penetrant metabotropic glutamate receptor 7 (mGlu7) negative allosteric modulator (NAM) that achieves exposure in cerebral spinal fluid (CSF) 2.5× above the in vitro IC50 at minimum effective doses (MEDs) of 3 mg/kg in preclinical anxiety models.
