Pyrimidone-based series of glucokinase activators with alternative donor–acceptor motif

• Published in: Bioorganic & medicinal chemistry letters 2013-08, Vol.23 (16), p.4571-4578
• Main Authors: Filipski, Kevin J., Guzman-Perez, Angel, Bian, Jianwei, Perreault, Christian, Aspnes, Gary E., Didiuk, Mary T., Dow, Robert L., Hank, Richard F., Jones, Christopher S., Maguire, Robert J., Tu, Meihua, Zeng, Dongxiang, Liu, Shenping, Knafels, John D., Litchfield, John, Atkinson, Karen, Derksen, David R., Bourbonais, Francis, Gajiwala, Ketan S., Hickey, Michael, Johnson, Theodore O., Humphries, Paul S., Pfefferkorn, Jeffrey A.
• Format: Article
• Language: English
• Subjects: Allosteric Regulation; Amino Acid Motifs; Animals; Binding Sites; chemistry; Enzyme Activators - chemistry; glucokinase; Glucokinase - metabolism; Glucokinase activator; Models, Molecular; noninsulin-dependent diabetes mellitus; pharmacokinetics; Pyrimidinones - chemical synthesis; Pyrimidinones - chemistry; Pyrimidone; Rats; therapeutics; Type 2 diabetes mellitus; X-ray diffraction
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.06.036

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.