1246891-80-4Relevant articles and documents
Design, synthesis, and structure-activity relationships of novel bicyclic azole-amines as negative allosteric modulators of metabotropic glutamate receptor 5
Burdi, Douglas F.,Hunt, Rachel,Fan, Lei,Hu, Tao,Wang, Jun,Guo, Zihong,Huang, Zhiqiang,Wu, Chengde,Hardy, Larry,Detheux, Michel,Orsini, Michael A.,Quinton, Maria S.,Lew, Robert,Spear, Kerry
experimental part, p. 7107 - 7118 (2010/12/25)
A novel series of diaryl bicyclic azole-amines that are potent selective negative modulators of metabotropic glutamate receptor 5 (mGluR5) were identified through rational design. An initial hit compound 5a of modest potency (IC50 = 1.2 μM) was synthesized. Evaluation of structure-activity relationships (SAR) on the left-hand side of the molecule revealed a preference for a 2-substituted pyridine group linked directly to the central heterocycle. Variation of the central azolo-amine portion of the molecule revealed a preference for the [4,5-c]-oxazoloazepine scaffold, while right-hand side variants showed a preference for ortho- and meta-substituted benzene rings linked directly to the tertiary amine of the saturated heterocycle. These iterations led to the synthesis of 29b, a potent (IC50 = 16 nM) and selective negative modulator that showed good brain penetrance, high receptor occupancy, and a duration of action greater than 1 h in rat when administered intraperitoneally. Formal PK studies in rat and Rhesus monkey revealed a short half-life that was attributable to high first-pass clearance.
