title: Discovery of (S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid as a hepatoselective glucokinase activator clinical candidate for treating type 2 diabetes mellitus.
abstract: Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due to activation of the enzyme at low glucose levels in the pancreas, leading to inappropriately excessive insulin secretion. It was therefore postulated that a liver selective activator may offer effective glycemic control with reduced hypoglycemia risk. Herein, we report structure-activity studies on a carboxylic acid containing series of glucokinase activators with preferential activity in hepatocytes versus pancreatic β-cells. These activators were designed to have low passive permeability thereby minimizing distribution into extrahepatic tissues; concurrently, they were also optimized as substrates for active liver uptake via members of the organic anion transporting polypeptide (OATP) family. These studies lead to the identification of 19 as a potent glucokinase activator with a greater than 50-fold liver-to-pancreas ratio of tissue distribution in rodent and non-rodent species. In preclinical diabetic animals, 19 was found to robustly lower fasting and postprandial glucose with no hypoglycemia, leading to its selection as a clinical development candidate for treating type 2 diabetes.
authors.affiliation: Cambridge Laboratories, Pfizer Worldwide Research & Development, 620 Memorial Drive, Cambridge, Massachusetts 02139, United States. jeffrey.a.pfefferkorn@pfizer.com
authors.forename: Jeffrey A
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authors.lastname: Pfefferkorn
authors.forename: Angel
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authors.lastname: Guzman-Perez
authors.forename: John
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authors.lastname: Litchfield
authors.forename: Robert
authors.initials: R
authors.lastname: Aiello
authors.forename: Judith L
authors.initials: JL
authors.lastname: Treadway
authors.forename: John
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authors.lastname: Pettersen
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authors.lastname: Minich
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Filipski
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Jones
authors.forename: Meihua
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authors.lastname: Tu
authors.forename: Gary
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authors.lastname: Aspnes
authors.forename: Hud
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authors.lastname: Risley
authors.forename: Jianwei
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authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Stevens
authors.forename: Patricia
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authors.lastname: Bourassa
authors.forename: Theresa
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authors.lastname: D'Aquila
authors.forename: Levenia
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authors.lastname: Baker
authors.forename: Nicole
authors.initials: N
authors.lastname: Barucci
authors.forename: Alan S
authors.initials: AS
authors.lastname: Robertson
authors.forename: Francis
authors.initials: F
authors.lastname: Bourbonais
authors.forename: David R
authors.initials: DR
authors.lastname: Derksen
authors.forename: Margit
authors.initials: M
authors.lastname: Macdougall
authors.forename: Over
authors.initials: O
authors.lastname: Cabrera
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Amanda Lee
authors.initials: AL
authors.lastname: Lapworth
authors.forename: James A
authors.initials: JA
authors.lastname: Landro
authors.forename: William J
authors.initials: WJ
authors.lastname: Zavadoski
authors.forename: Karen
authors.initials: K
authors.lastname: Atkinson
authors.forename: Nahor
authors.initials: N
authors.lastname: Haddish-Berhane
authors.forename: Beijing
authors.initials: B
authors.lastname: Tan
authors.forename: Lili
authors.initials: L
authors.lastname: Yao
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Kosa
authors.forename: Manthena V
authors.initials: MV
authors.lastname: Varma
authors.forename: Bo
authors.initials: B
authors.lastname: Feng
authors.forename: David B
authors.initials: DB
authors.lastname: Duignan
authors.forename: Ayman
authors.initials: A
authors.lastname: El-Kattan
authors.forename: Sharad
authors.initials: S
authors.lastname: Murdande
authors.forename: Shenping
authors.initials: S
authors.lastname: Liu
authors.forename: Mark
authors.initials: M
authors.lastname: Ammirati
authors.forename: John
authors.initials: J
authors.lastname: Knafels
authors.forename: Paul
authors.initials: P
authors.lastname: Dasilva-Jardine
authors.forename: Laurel
authors.initials: L
authors.lastname: Sweet
authors.forename: Spiros
authors.initials: S
authors.lastname: Liras
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Rolph
mesh_terms: D000495:Allosteric Site; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004285:Dogs; D020536:Enzyme Activators / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D005941:Glucokinase / Q000378:metabolism*; D000882:Haplorhini; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D009539:Nicotinic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D027361:Organic Anion Transporters / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D001786:Blood Glucose; D020536:Enzyme Activators; D007004:Hypoglycemic Agents; D007093:Imidazoles; D009539:Nicotinic Acids; D027361:Organic Anion Transporters; C571532:6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid; D005941:Glucokinase