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.
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| http://dx.doi.org/10.1021/ml400027y | DOI Listing |
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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.
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.
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