The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu4 PAM development candidate.

Graphical abstract Highlights • First description of the SAR that led to the discovery of VU2957 (Valiglurax). • Valiglurax is only the second mGlu4 PAM clinical candidate for Parkinson's disease. • The new series afford improvements in protein binding, half-life in vivo , CNS penetration and oral bioavailability. • Highlights subtle differences in positioning of hydrogen-bond acceptors and impact on CNS penetration/P-gp liability. Abstract This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu 4 positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate. Here, we detail the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as subtle structural changes affecting overall physiochemical/DMPK properties and CNS penetration). [ABSTRACT FROM AUTHOR]