Discovery of an intravenous hepatoselective glucokinase activator for the treatment of inpatient hyperglycemia.
Glucokinase (hexokinase IV) continues to be a compelling target for the treatment of type 2 diabetes given the wealth of supporting human genetics data and numerous reports of robust clinical glucose lowering in patients treated with small molecule allosteric activators. Recent work has demonstrated the ability of hepatoselective activators to deliver glucose lowering efficacy with minimal risk of hypoglycemia. While orally administered agents require a considerable degree of passive permeability to promote suitable exposures, there is no such restriction on intravenously delivered drugs. Therefore, minimization of membrane diffusion in the context of an intravenously agent should ensure optimal hepatic targeting and therapeutic index. This work details the identification a hepatoselective GKA exhibiting the aforementioned properties.
Cambridge Laboratories, Pfizer Worldwide Research & Development, 620 Memorial Drive, Cambridge, MA 02139, United States. Electronic address: bdsteven@gmail.com.
Benjamin D
BD
Stevens
John
J
Litchfield
Jeffrey A
JA
Pfefferkorn
Karen
K
Atkinson
Christian
C
Perreault
Paul
P
Amor
Kevin
K
Bahnck
Martin A
MA
Berliner
Jessica
J
Calloway
Anthony
A
Carlo
David R
DR
Derksen
Kevin J
KJ
Filipski
Mike
M
Gumkowski
Charanjeet
C
Jassal
Margit
M
MacDougall
Brendan
B
Murphy
Paul
P
Nkansah
John
J
Pettersen
Charles
C
Rotter
Yan
Y
Zhang
D000494:Allosteric Regulation; D000818:Animals; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical; D020536:Enzyme Activators / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D005941:Glucokinase / Q000737:chemistry* / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000201:enzymology; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D007093:Imidazoles / Q000737:chemistry; D007275:Injections, Intravenous; D009525:Niacin / Q000031:analogs & derivatives / Q000737:chemistry; D051381:Rats; D014018:Tissue Distribution
C000597952:6-(2-(4-(cyclobutanesulfonyl)-1H-imidazol-1-yl)-3-cyclopentylpropanamido)pyridine-3-carboxylic acid; D020536:Enzyme Activators; D007004:Hypoglycemic Agents; D007093:Imidazoles; D009525:Niacin; C029899:imidazole; D005941:Glucokinase
Allosteric; Diabetes; Glucokinase; Hepatoselective; OATP