1.
Bioorg Med Chem Lett
; 29(10): 1211-1214, 2019 05 15.
Artículo
en Inglés
| MEDLINE
| ID: mdl-30910459
RESUMEN
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).