OPTIMIZATION OF NAMPT (NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE) ACTIVATORS: DISCOVERY OF N,N-DIETHYL-1,2-BENZOXAZOLE-3-CARBOXAMIDE DERIVATIVES AS POTENT NAMPT ACTIVATORS WITH MITIGATED MUTAGENIC RISKS

DS68702229, a potent NAMPT activator developed from HTS followed by a hit-to-lead campaign, is a promising candidate compound that significantly reduced body weight when orally administered to mice with high fat diet-induced obesity. However, in vitro toxicology profiling of DS68702229 revealed bacterial mutagenicity using Salmonella typhimurium TA98 and TA100 strains upon S9 activation. Hypothesizing that DNA intercalation is the likely cause, we employed several approaches to disrupt the putative DNA intercalation, including modulation of the molecular shape. Our efforts culminated in the discovery of compounds 20k and 20l, which increased intracellular NAD(+) levels in a cell-based assay without inducing mutagenicity, along with acceptable plasma exposure in mice after oral administration.