title: Identification of RO4597014, a Glucokinase Activator Studied in the Clinic for the Treatment of Type 2 Diabetes.
abstract: To resolve the metabolite redox cycling associated with our earlier clinical compound 2, we carried out lead optimization of lead molecule 1. Compound 4 showed improved lipophilic ligand efficiency and demonstrated robust glucose lowering in diet-induced obese mice without a liability in predictive preclinical drug safety studies. Thus, it was selected as a clinical candidate and further studied in type 2 diabetic patients. Clinical data suggests no evidence of metabolite cycling, which is consistent with the preclinical profiling of metabolism.
authors.affiliation: Departments of Discovery Chemistry, Pharmaceutical and Analytical Research, Metabolic and Vascular Diseases, Drug Metabolism and Pharmacokinetics, Process Research, Clinical Pharmacology, Hoffmann-La Roche , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Departments of Discovery Chemistry, Pharmaceutical and Analytical Research, Metabolic and Vascular Diseases, Drug Metabolism and Pharmacokinetics, Process Research, Clinical Pharmacology, Hoffmann-La Roche , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Corbett
authors.affiliation: Departments of Discovery Chemistry, Pharmaceutical and Analytical Research, Metabolic and Vascular Diseases, Drug Metabolism and Pharmacokinetics, Process Research, Clinical Pharmacology, Hoffmann-La Roche , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Berthel
authors.affiliation: Departments of Discovery Chemistry, Pharmaceutical and Analytical Research, Metabolic and Vascular Diseases, Drug Metabolism and Pharmacokinetics, Process Research, Clinical Pharmacology, Hoffmann-La Roche , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Duk Soon
authors.initials: DS
authors.lastname: Choi
authors.affiliation: Departments of Discovery Chemistry, Pharmaceutical and Analytical Research, Metabolic and Vascular Diseases, Drug Metabolism and Pharmacokinetics, Process Research, Clinical Pharmacology, Hoffmann-La Roche , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Dvorozniak
authors.affiliation: Departments of Discovery Chemistry, Pharmaceutical and Analytical Research, Metabolic and Vascular Diseases, Drug Metabolism and Pharmacokinetics, Process Research, Clinical Pharmacology, Hoffmann-La Roche , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Wanping
authors.initials: W
authors.lastname: Geng
authors.affiliation: Departments of Discovery Chemistry, Pharmaceutical and Analytical Research, Metabolic and Vascular Diseases, Drug Metabolism and Pharmacokinetics, Process Research, Clinical Pharmacology, Hoffmann-La Roche , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Gillespie
authors.affiliation: Departments of Discovery Chemistry, Pharmaceutical and Analytical Research, Metabolic and Vascular Diseases, Drug Metabolism and Pharmacokinetics, Process Research, Clinical Pharmacology, Hoffmann-La Roche , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Guertin
authors.affiliation: Departments of Discovery Chemistry, Pharmaceutical and Analytical Research, Metabolic and Vascular Diseases, Drug Metabolism and Pharmacokinetics, Process Research, Clinical Pharmacology, Hoffmann-La Roche , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Nancy-Ellen
authors.initials: NE
authors.lastname: Haynes
authors.affiliation: Departments of Discovery Chemistry, Pharmaceutical and Analytical Research, Metabolic and Vascular Diseases, Drug Metabolism and Pharmacokinetics, Process Research, Clinical Pharmacology, Hoffmann-La Roche , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Kester
authors.affiliation: Departments of Discovery Chemistry, Pharmaceutical and Analytical Research, Metabolic and Vascular Diseases, Drug Metabolism and Pharmacokinetics, Process Research, Clinical Pharmacology, Hoffmann-La Roche , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Francis A
authors.initials: FA
authors.lastname: Mennona
authors.affiliation: Departments of Discovery Chemistry, Pharmaceutical and Analytical Research, Metabolic and Vascular Diseases, Drug Metabolism and Pharmacokinetics, Process Research, Clinical Pharmacology, Hoffmann-La Roche , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: David
authors.initials: D
authors.lastname: Moore
authors.affiliation: Departments of Discovery Chemistry, Pharmaceutical and Analytical Research, Metabolic and Vascular Diseases, Drug Metabolism and Pharmacokinetics, Process Research, Clinical Pharmacology, Hoffmann-La Roche , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Jagdish
authors.initials: J
authors.lastname: Racha
authors.affiliation: Departments of Discovery Chemistry, Pharmaceutical and Analytical Research, Metabolic and Vascular Diseases, Drug Metabolism and Pharmacokinetics, Process Research, Clinical Pharmacology, Hoffmann-La Roche , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Roumen
authors.initials: R
authors.lastname: Radinov
authors.affiliation: Departments of Discovery Chemistry, Pharmaceutical and Analytical Research, Metabolic and Vascular Diseases, Drug Metabolism and Pharmacokinetics, Process Research, Clinical Pharmacology, Hoffmann-La Roche , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Ramakanth
authors.initials: R
authors.lastname: Sarabu
authors.affiliation: Departments of Discovery Chemistry, Pharmaceutical and Analytical Research, Metabolic and Vascular Diseases, Drug Metabolism and Pharmacokinetics, Process Research, Clinical Pharmacology, Hoffmann-La Roche , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Scott
authors.affiliation: Departments of Discovery Chemistry, Pharmaceutical and Analytical Research, Metabolic and Vascular Diseases, Drug Metabolism and Pharmacokinetics, Process Research, Clinical Pharmacology, Hoffmann-La Roche , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Grimsby
authors.affiliation: Departments of Discovery Chemistry, Pharmaceutical and Analytical Research, Metabolic and Vascular Diseases, Drug Metabolism and Pharmacokinetics, Process Research, Clinical Pharmacology, Hoffmann-La Roche , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
authors.forename: Navita L
authors.initials: NL
authors.lastname: Mallalieu
keywords: Glucokinase activator; lipophilic ligand efficiency; metabolite; redox cycling; type 2 diabetes