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Burdi DF, Hunt R, Fan L, et al. Design, synthesis, and structure-activity relationships of novel bicyclic azole-amines as negative allosteric modulators of metabotropic glutamate receptor 5. J Med Chem. 2010;53(19):7107-18doi: 10.1021/jm100736h.
Burdi, D. F., Hunt, R., Fan, L., Hu, T., Wang, J., Guo, Z., Huang, Z., Wu, C., Hardy, L., Detheux, M., Orsini, M. A., Quinton, M. S., Lew, R., & Spear, K. (2010). Design, synthesis, and structure-activity relationships of novel bicyclic azole-amines as negative allosteric modulators of metabotropic glutamate receptor 5. Journal of medicinal chemistry, 53(19), 7107-18. https://doi.org/10.1021/jm100736h
Burdi, Douglas F, et al. "Design, synthesis, and structure-activity relationships of novel bicyclic azole-amines as negative allosteric modulators of metabotropic glutamate receptor 5." Journal of medicinal chemistry vol. 53,19 (2010): 7107-18. doi: https://doi.org/10.1021/jm100736h
Burdi DF, Hunt R, Fan L, Hu T, Wang J, Guo Z, Huang Z, Wu C, Hardy L, Detheux M, Orsini MA, Quinton MS, Lew R, Spear K. Design, synthesis, and structure-activity relationships of novel bicyclic azole-amines as negative allosteric modulators of metabotropic glutamate receptor 5. J Med Chem. 2010 Oct 14;53(19):7107-18. doi: 10.1021/jm100736h. PMID: 20809633.
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J Med Chem. 2010 Oct 14;53(19):7107-18. doi: 10.1021/jm100736h.

Design, synthesis, and structure-activity relationships of novel bicyclic azole-amines as negative allosteric modulators of metabotropic glutamate receptor 5.

Journal of medicinal chemistry

Douglas F Burdi, Rachel Hunt, Lei Fan, Tao Hu, Jun Wang, Zihong Guo, Zhiqiang Huang, Chengde Wu, Larry Hardy, Michel Detheux, Michael A Orsini, Maria S Quinton, Robert Lew, Kerry Spear

Affiliations

  1. Discovery & Early Clinical Research, Sepracor Inc., 84 Waterford Drive, Marlborough, Massachusetts 01752, USA. [email protected]

PMID: 20809633 DOI: 10.1021/jm100736h

Abstract

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 (IC(50) = 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 (IC(50) = 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.

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