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  • Title: Use of small-molecule crystal structures to address solubility in a novel series of G protein coupled receptor 119 agonists: optimization of a lead and in vivo evaluation.
    Author: Scott JS, Birch AM, Brocklehurst KJ, Broo A, Brown HS, Butlin RJ, Clarke DS, Davidsson O, Ertan A, Goldberg K, Groombridge SD, Hudson JA, Laber D, Leach AG, Macfaul PA, McKerrecher D, Pickup A, Schofield P, Svensson PH, Sörme P, Teague J.
    Journal: J Med Chem; 2012 Jun 14; 55(11):5361-79. PubMed ID: 22545772.
    Abstract:
    G protein coupled receptor 119 (GPR119) is viewed as an attractive target for the treatment of type 2 diabetes and other elements of the metabolic syndrome. During a program toward discovering agonists of GPR119, we herein describe optimization of an initial lead compound, 2, into a development candidate, 42. A key challenge in this program of work was the insolubility of the lead compound. Small-molecule crystallography was utilized to understand the intermolecular interactions in the solid state and resulted in a switch from an aryl sulphone to a 3-cyanopyridyl motif. The compound was shown to be effective in wild-type but not knockout animals, confirming that the biological effects were due to GPR119 agonism.
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