Pyridones as glucokinase activators: identification of a unique metabolic liability of the 4-sulfonyl-2-pyridone heterocycle.
A promising area of novel anti-diabetic therapy involves identification of small molecule activators of the glucokinase enzyme to reduce blood glucose and normalize glucose stimulated insulin secretion. Herein, we report the identification and optimization of a series of 4-sulfonyl-2-pyridone activators. The activators were evaluated for in vitro biochemical activation and pharmacokinetic properties. As part of these efforts, a unique metabolic liability of the 4-sulfonyl-2-pyridone ring system was identified wherein this heterocycle readily undergoes conjugation with glutathione under non-enzymatic conditions.
Pfefferkorn
Jeffrey A
JA
Pfizer Global Research & Development, Groton Laboratories, Eastern Point Road, Groton, CT 06344, USA. jeffrey.a.pfefferkorn@pfizer.com
Lou
Jihong
J
Minich
Martha L
ML
Filipski
Kevin J
KJ
He
Mingying
M
Zhou
Ru
R
Ahmed
Syed
S
Benbow
John
J
Perez
Angel-Guzman
AG
Tu
Meihua
M
Litchfield
John
J
Sharma
Raman
R
Metzler
Karen
K
Bourbonais
Francis
F
Huang
Cong
C
Beebe
David A
DA
Oates
Peter J
PJ
D000818:Animals; D001786:Blood Glucose; D004789:Enzyme Activation / Q000187:drug effects; D005941:Glucokinase / Q000187:drug effects*; D005978:Glutathione / Q000737:chemistry; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D008862:Microsomes, Liver / Q000378:metabolism; D011728:Pyridones / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D011728:Pyridones; D005941:Glucokinase; D005978:Glutathione