Discovery of a series of indan carboxylic acid glycogen phosphorylase inhibitors.
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.
Bennett
Stuart N L
SN
AstraZeneca, Medicinal Chemistry, Cardiovascular and Gastrointestinal Research Area, Alderley Park, Macclesfield, Cheshire, UK.
Campbell
Andrew D
AD
Hancock
Andrew
A
Johnstone
Craig
C
Kenny
Peter W
PW
Pickup
Adrian
A
Plowright
Alleyn T
AT
Selmi
Nidhal
N
Simpson
Iain
I
Stocker
Andy
A
Whalley
David P
DP
Whittamore
Paul R O
PR
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
D002264:Carboxylic Acids; D007004:Hypoglycemic Agents; D007189:Indans; D025001:Glycogen Phosphorylase, Liver Form; C093582:indan