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

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• 作者：James S. Scott ; Alan M. Birch ; Katy J. Brocklehurst ; Anders Broo ; Hayley S. Brown ; Roger J. Butlin ; David S. Clarke ; 脰jvind Davidsson ; Anne Ertan ; Kristin Goldberg ; Sam D. Groombridge ; Julian A. Hudson ; David Laber ; Andrew G. Leach ; Philip A. MacFaul ; Darren McKerrecher ; Adrian Pickup ; Paul Schofield ; Per H. Svensson ; Pernilla S枚rme ; Joanne Teague
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：June 14, 2012
• 年：2012
• 卷：55
• 期：11
• 页码：5361-5379
• 全文大小：842K
• 年卷期：v.55,no.11(June 14, 2012)
• ISSN：1520-4804

文摘

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.