title: Conformational restriction in a series of GPR119 agonists: differences in pharmacology between mouse and human.
abstract: A series of conformationally restricted GPR119 agonists were prepared based around a 3,8-diazabicyclo[3.2.1]octane scaffold. Examples were found to have markedly different pharmacology in mouse and human despite similar levels of binding to the receptor. This highlights the large effects on GPCR phamacology that can result from small structural changes in the ligand, together with inter-species differences between receptors.
authors.affiliation: Cardiovascular & Gastrointestinal Innovative Medicines Unit, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. jamie.scott@astrazeneca.com
authors.forename: James S
authors.initials: JS
authors.lastname: Scott
authors.forename: Katy J
authors.initials: KJ
authors.lastname: Brocklehurst
authors.forename: Hayley S
authors.initials: HS
authors.lastname: Brown
authors.forename: David S
authors.initials: DS
authors.lastname: Clarke
authors.forename: Helen
authors.initials: H
authors.lastname: Coe
authors.forename: Sam D
authors.initials: SD
authors.lastname: Groombridge
authors.forename: David
authors.initials: D
authors.lastname: Laber
authors.forename: Philip A
authors.initials: PA
authors.lastname: MacFaul
authors.forename: Darren
authors.initials: D
authors.lastname: McKerrecher
authors.forename: Paul
authors.initials: P
authors.lastname: Schofield
mesh_terms: D000818:Animals; D001682:Biological Availability; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D002463:Cell Membrane Permeability / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004285:Dogs; D006207:Half-Life; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D011485:Protein Binding; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C519854:GPR119 protein, human; D006574:Heterocyclic Compounds, 2-Ring; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D000242:Cyclic AMP