Discovery of potent and efficacious cyanoguanidine-containing nicotinamide phosphoribosyltransferase (Nampt) inhibitors

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Abstract

A co-crystal structure of amide-containing compound (4) in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein and molecular modeling were utilized to design and discover a potent novel cyanoguanidine-containing inhibitor bearing a sulfone moiety (5, Nampt Biochemical IC50 = 2.5 nM, A2780 cell proliferation IC50 = 9.7 nM). Further SAR exploration identified several additional cyanoguanidine-containing compounds with high potency and good microsomal stability. Among these, compound 15 was selected for in vivo profiling and demonstrated good oral exposure in mice. It also exhibited excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model. The co-crystal structure of this compound in complex with the NAMPT protein was also determined.

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Acknowledgments

We acknowledge Forma’s high speed synthesis group for their synthetic contributions and the ADME group for generating the microsomal and solubility data, Shohini Ganguly and Rashida Garcia-Dancey for helping to generate the cellular data, Lakshmanan Manikandan, Saradhi Vijay, and Danilal C. Sharma for generating the in vivo PK and efficacy data, Agilent Technologies (Woburn, MA) for generating the Rapidfire LCMS data, and Professor Yigong Shi’s group (Tsinghua University, Beijing, China) for

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