Discovery of piragliatin--first glucokinase activator studied in type 2 diabetic patients.
Glucokinase (GK) activation as a potential strategy to treat type 2 diabetes (T2D) is well recognized. Compound 1, a glucokinase activator (GKA) lead that we have previously disclosed, caused reversible hepatic lipidosis in repeat-dose toxicology studies. We hypothesized that the hepatic lipidosis was due to the structure-based toxicity and later established that it was due to the formation of a thiourea metabolite, 2. Subsequent SAR studies of 1 led to the identification of a pyrazine-based lead analogue 3, lacking the thiazole moiety. In vivo metabolite identification studies, followed by the independent synthesis and profiling of the cyclopentyl keto- and hydroxyl- metabolites of 3, led to the selection of piragliatin, 4, as the clinical lead. Piragliatin was found to lower pre- and postprandial glucose levels, improve the insulin secretory profile, increase β-cell sensitivity to glucose, and decrease hepatic glucose output in patients with T2D.
Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, DTA Metabolism, 340 Kingsland Street, Nutley, New Jersey 07110, United States. ramakanth.sarabu@roche.com
Ramakanth
R
Sarabu
Fred T
FT
Bizzarro
Wendy L
WL
Corbett
Mark T
MT
Dvorozniak
Wanping
W
Geng
Joseph F
JF
Grippo
Nancy-Ellen
NE
Haynes
Stanley
S
Hutchings
Lisa
L
Garofalo
Kevin R
KR
Guertin
Darryl W
DW
Hilliard
Marek
M
Kabat
Robert F
RF
Kester
Wang
W
Ka
Zhenmin
Z
Liang
Paige E
PE
Mahaney
Linda
L
Marcus
Franz M
FM
Matschinsky
David
D
Moore
Jagdish
J
Racha
Roumen
R
Radinov
Yi
Y
Ren
Lida
L
Qi
Michael
M
Pignatello
Cheryl L
CL
Spence
Thomas
T
Steele
John
J
Tengi
Joseph
J
Grimsby
D000818:Animals; D044482:Benzeneacetamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004285:Dogs; D020536:Enzyme Activators / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D005941:Glucokinase / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008064:Lipidoses / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019518:Postprandial Period; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D044482:Benzeneacetamides; D020536:Enzyme Activators; D007004:Hypoglycemic Agents; C553963:piragliatin; D005941:Glucokinase; D005947:Glucose