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.
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.
authors.affiliation: Cardiovascular & Gastrointestinal Innovative Medicines Unit, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom. jamie.scott@astrazeneca.com
authors.forename: James S
authors.initials: JS
authors.lastname: Scott
authors.forename: Alan M
authors.initials: AM
authors.lastname: Birch
authors.forename: Katy J
authors.initials: KJ
authors.lastname: Brocklehurst
authors.forename: Anders
authors.initials: A
authors.lastname: Broo
authors.forename: Hayley S
authors.initials: HS
authors.lastname: Brown
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Butlin
authors.forename: David S
authors.initials: DS
authors.lastname: Clarke
authors.forename: Ojvind
authors.initials: O
authors.lastname: Davidsson
authors.forename: Anne
authors.initials: A
authors.lastname: Ertan
authors.forename: Kristin
authors.initials: K
authors.lastname: Goldberg
authors.forename: Sam D
authors.initials: SD
authors.lastname: Groombridge
authors.forename: Julian A
authors.initials: JA
authors.lastname: Hudson
authors.forename: David
authors.initials: D
authors.lastname: Laber
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Leach
authors.forename: Philip A
authors.initials: PA
authors.lastname: Macfaul
authors.forename: Darren
authors.initials: D
authors.lastname: McKerrecher
authors.forename: Adrian
authors.initials: A
authors.lastname: Pickup
authors.forename: Paul
authors.initials: P
authors.lastname: Schofield
authors.forename: Per H
authors.initials: PH
authors.lastname: Svensson
authors.forename: Pernilla
authors.initials: P
authors.lastname: Sörme
authors.forename: Joanne
authors.initials: J
authors.lastname: Teague
mesh_terms: D000818:Animals; D001682:Biological Availability; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004285:Dogs; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C575282:4-(((2-(2-methyl-4-(5-(1-methylethyl)-1,2,4-oxadiazol-3-yl)piperazin-1-yl)pyrimidin-5-yl)oxy)methyl)pyridine-3-carbonitrile; D002219:Carbamates; C519854:GPR119 protein, human; C516207:Gpr119 protein, mouse; D010069:Oxadiazoles; D010880:Piperidines; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; D054852:Small Molecule Libraries; D013450:Sulfones