Surveying heterocycles as amide bioisosteres within a series of mGlu7 NAMs: Discovery of VU6019278.

Graphical abstract Highlights • Novel series of selective and CNS penetrant mGlu 7 NAMs. • Identified a 1,3,4-oxadiazole as biosiostere for a labile amide linker. • Iterative libraries quickly optimized this novel tricyclic series. Abstract 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 mGlu 7 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 mGlu 7 NAM chemotype led to the discovery of VU6019278, a potent mGlu 7 NAM (IC 50 = 501 nM, 6.3% L-AP 4 Min) with favorable plasma protein binding (rat f u = 0.10), low predicted hepatic clearance (rat CL hep = 27.7 mL/min/kg) and high CNS penetration (rat K p = 4.9, K p,uu = 0.65). [ABSTRACT FROM AUTHOR]