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Published on: December 25, 2021
Pyrimidone-based series of glucokinase activators with alternative donor-acceptor motif
Kevin J Filipski1, Angel Guzman-Perez, Jianwei Bian
1Cardiovascular, Metabolic, and Endocrine Diseases Chemistry, Pfizer Worldwide Research and Development, 620 Memorial Dr, Cambridge, MA 02139, USA. kevin.filipski@pfizer.com
Abstract:
Glucokinase activators are a class of experimental agents under investigation as a therapy for Type 2 diabetes mellitus. An X-ray crystal structure of a modestly potent agent revealed the potential to substitute the common heterocyclic amide donor-acceptor motif for a pyridone moiety. We have successfully demonstrated that both pyridone and pyrimidone heterocycles can be used as a potent donor-acceptor substituent. Several sub-micromolar analogs that possess the desired partial activator profile were synthesized and characterized. Unfortunately, the most potent activators suffered from sub-optimal pharmacokinetic properties. Nonetheless, these donor-acceptor motifs may find utility in other glucokinase activator series or beyond.
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