title: Discovery of liver-directed glucokinase activator having anti-hyperglycemic effect without hypoglycemia.
abstract: Glucokinase activators (GKAs) are among the emerging drug candidates for the treatment of type 2 diabetes (T2D). Despite effective blood glucose lowering in clinical trials, many pan-GKAs "acting both in pancreas and liver" have been discontinued from clinical development mainly because of their potential to cause hypoglycemia. Pan-GKAs over sensitize pancreatic GK, resulting in insulin secretion even at sub-normoglycemic level which might be a possible explanation for hypoglycemia. An alternative approach to minimize the risk of hypoglycemia is to use liver-directed GKAs, which are reported to be advancing well in clinical development. Here, we report the discovery and structure-activity relationship (SAR) studies on a novel 2-phenoxy-acetamide series with the aim of identifying a liver-directed GKA. Incorporation of a carboxylic acid moiety as an active hepatocyte uptake recognizing element at appropriate position of 2-phenoxy-acetamide core led to the identification of 26, a potent GKA with predominant liver-directed pharmacokinetics in mice. Compound 26 on oral administration significantly reduced blood glucose levels during an oral glucose tolerance test (oGTT) performed in diet-induced obese (DIO) mice, while showing no sign of hypoglycemia in normal C57 mice over a 10-fold dose range, even when dosed at fasted condition. Together, these data demonstrate a liver-directed GKA has beneficial effect on glucose homeostasis with reduced risk of hypoglycemia.
authors.affiliation: Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India. Electronic address: anil.deshpande@advinus.com.
authors.forename: Anil M
authors.initials: AM
authors.lastname: Deshpande
authors.affiliation: Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Debnath
authors.initials: D
authors.lastname: Bhuniya
authors.affiliation: Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: De
authors.affiliation: Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Bhavesh
authors.initials: B
authors.lastname: Dave
authors.affiliation: Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Vinod P
authors.initials: VP
authors.lastname: Vyavahare
authors.affiliation: Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Santosh H
authors.initials: SH
authors.lastname: Kurhade
authors.affiliation: Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Sachin R
authors.initials: SR
authors.lastname: Kandalkar
authors.affiliation: Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Keshav P
authors.initials: KP
authors.lastname: Naik
authors.affiliation: Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Balasaheb S
authors.initials: BS
authors.lastname: Kobal
authors.affiliation: Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Rahul D
authors.initials: RD
authors.lastname: Kaduskar
authors.affiliation: Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Sujay
authors.initials: S
authors.lastname: Basu
authors.affiliation: Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Jain
authors.affiliation: Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Pratima
authors.initials: P
authors.lastname: Patil
authors.affiliation: Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Chaturvedi Joshi
authors.affiliation: Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Bhat
authors.affiliation: Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Amol A
authors.initials: AA
authors.lastname: Raje
authors.affiliation: Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Satyanarayana
authors.initials: S
authors.lastname: Reddy
authors.affiliation: Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Jayasagar
authors.initials: J
authors.lastname: Gundu
authors.affiliation: Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Vamsi
authors.initials: V
authors.lastname: Madgula
authors.affiliation: Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Suhas
authors.initials: S
authors.lastname: Tambe
authors.affiliation: Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Prasad
authors.initials: P
authors.lastname: Shitole
authors.affiliation: Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Umrani
authors.affiliation: Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Anita
authors.initials: A
authors.lastname: Chugh
authors.affiliation: Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Venkata P
authors.initials: VP
authors.lastname: Palle
authors.affiliation: Advinus Therapeutics Ltd., Drug Discovery Facility, Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjewadi, Pune 411 057, India.
authors.forename: Kasim A
authors.initials: KA
authors.lastname: Mookhtiar
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D020536:Enzyme Activators / Q000009:adverse effects / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D005941:Glucokinase / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D007003:Hypoglycemia / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008820:Mice, Obese; D062105:Molecular Docking Simulation; D051381:Rats
chemical_list: D001786:Blood Glucose; D020536:Enzyme Activators; D007004:Hypoglycemic Agents; D005941:Glucokinase
keywords: 2-Phenoxy-acetamide; Activator; Anti-hyperglycemic; Glucokinase; Liver-directed