• Garcia-Barrantes PM, Cho HP, Blobaum AL, Niswender CM, Conn PJ, Lindsley CW. Lead optimization of the VU0486321 series of mGlu1 PAMs. Part 3. Engineering plasma stability by discovery and optimization of isoindolinone analogs. Bioorganic & medicinal chemistry letters. 2016 Apr 15;26(8). 1869-72. PMID: 26988302 [PubMed].


This Letter describes the further lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs), focused on addressing the recurrent issue of plasma instability of the phthalimide moiety. Here, we evaluated a number of phthalimide bioisosteres, and ultimately identified isoindolinones as the ideal replacement that effectively address plasma instability, while maintaining acceptable mGlu1 PAM potency, DMPK profile, CNS penetration and mGluR selectivity.