title: Discovery of a series of indan carboxylic acid glycogen phosphorylase inhibitors.
abstract: A series of carboxylic acid glycogen phosphorylase inhibitors, which have potential as oral antidiabetic agents, is described. Defining and applying simple physicochemical design criteria was used to assess the opportunity and to focus synthetic efforts on compounds with the greatest probability of success. The study led to compound 17, which exhibits a good balance of properties including potent inhibition of recombinant human liver glycogen phosphorylase in vitro, a good DMPK profile including excellent bioavailability and low clearance and good in vivo activity in a glucagon challenge model of diabetes in Zucker rats.
authors.affiliation: AstraZeneca, Medicinal Chemistry, Cardiovascular and Gastrointestinal Research Area, Alderley Park, Macclesfield, Cheshire, UK.
authors.forename: Stuart N L
authors.initials: SN
authors.lastname: Bennett
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Campbell
authors.forename: Andrew
authors.initials: A
authors.lastname: Hancock
authors.forename: Craig
authors.initials: C
authors.lastname: Johnstone
authors.forename: Peter W
authors.initials: PW
authors.lastname: Kenny
authors.forename: Adrian
authors.initials: A
authors.lastname: Pickup
authors.forename: Alleyn T
authors.initials: AT
authors.lastname: Plowright
authors.forename: Nidhal
authors.initials: N
authors.lastname: Selmi
authors.forename: Iain
authors.initials: I
authors.lastname: Simpson
authors.forename: Andy
authors.initials: A
authors.lastname: Stocker
authors.forename: David P
authors.initials: DP
authors.lastname: Whalley
authors.forename: Paul R O
authors.initials: PR
authors.lastname: Whittamore
mesh_terms: D000818:Animals; D001682:Biological Availability; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D055808:Drug Discovery; D025001:Glycogen Phosphorylase, Liver Form / Q000037:antagonists & inhibitors*; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000494:pharmacology; D007189:Indans / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011924:Rats, Zucker
chemical_list: D002264:Carboxylic Acids; D007004:Hypoglycemic Agents; D007189:Indans; D025001:Glycogen Phosphorylase, Liver Form; C093582:indan