Optimisation of aqueous solubility in a series of G protein coupled receptor 119 (GPR119) agonists

James S. Scott; Alan M. Birch; Katy J. Brocklehurst; Hayley S. Brown; Kristin Goldberg; Sam D. Groombridge; Julian A. Hudson; Andrew G. Leach; Philip A. MacFaul; Darren McKerrecher; Ruth Poultney; Paul Schofield; Per H. Svensson

doi:10.1039/C2MD20130E

Optimisation of aqueous solubility in a series of G protein coupled receptor 119 (GPR119) agonists†‡

James S. Scott,*^a Alan M. Birch,^a Katy J. Brocklehurst,^a Hayley S. Brown,^a Kristin Goldberg,^a Sam D. Groombridge,^a Julian A. Hudson,^a Andrew G. Leach,^a Philip A. MacFaul,^a Darren McKerrecher,^a Ruth Poultney,^a Paul Schofield^a and Per H. Svensson^b

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^a Cardiovascular & Gastrointestinal Innovative Medicines Unit, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UK
E-mail: jamie.scott@astrazeneca.com
Fax: +44 (0)1625 516667
Tel: +44 (0)1625 232567

^b Department of Applied Physical Chemistry, Royal Institute of Technology, SE-100 44 Stockholm, Sweden

Abstract

Improving aqueous solubility is a challenge frequently faced within drug discovery programs. Herein we describe increases in solubility in two sub-series of GPR119 agonists through reduction of lipophilicity together with hydrogen bond acceptor modulation. Small molecule X-ray crystallography was utilised to investigate effects on solid state interactions.

MedChemComm

Optimisation of aqueous solubility in a series of G protein coupled receptor 119 (GPR119) agonists†‡

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Optimisation of aqueous solubility in a series of G protein coupled receptor 119 (GPR119) agonists

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