- The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu4 PAM development candidate.
The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu4 PAM development candidate.
Bioorganic & medicinal chemistry letters (2018-12-07)
Joseph D Panarese, Darren W Engers, Yong-Jin Wu, Jason M Guernon, Aspen Chun, Alison R Gregro, Aaron M Bender, Rory A Capstick, Joshua M Wieting, Joanne J Bronson, John E Macor, Ryan Westphal, Matthew Soars, Julie E Engers, Andrew S Felts, Alice L Rodriguez, Kyle A Emmitte, Carrie K Jones, Anna L Blobaum, P Jeffrey Conn, Colleen M Niswender, Corey R Hopkins, Craig W Lindsley
PMID30503632
摘要
This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu4 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).
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