Preclinical Assessment of the ADME, Efficacy and Drug-Drug Interaction Potential of a Novel NAMPT Inhibitor.

GNE-617 (N-(4-((3,5-difluorophenyl)sulfonyl)benzyl)imidazo[1,2-a]pyridine-6-carboxamide) is a potent, selective nicotinamide phosphoribosyltransferase (NAMPT) inhibitor being explored as a potential treatment for human cancers.Plasma clearance was low in monkeys and dogs (9.14mL min(-1)kg(-1) and 4.62mL min(-1)kg(-1), respectively) and moderate in mice and rats (36.4mL min(-1)kg(-1) and 19.3mL min(-1)kg(-1), respectively). Oral bioavailability in mice, rats, monkeys and dogs was 29.7, 33.9, 29.4 and 65.2%, respectively.Allometric scaling predicted a low clearance of 3.3mL min(-1)kg(-1) and a volume of distribution of 1.3L kg(-1) in human.Efficacy (57% tumor growth inhibition) in Colo-205 CRC tumor xenograft mice was observed at an oral dose of 15mg/kg BID (AUC=10.4 mu Mh).Plasma protein binding was moderately high. GNE-617 was stable to moderately stable in vitro. Main human metabolites identified in human hepatocytes were formed primarily by CYP3A4/5. Transporter studies suggested that GNE-617 is likely a substrate for MDR1 but not for BCRP.Simcyp((R)) simulations suggested a low (CYP2C9 and CYP2C8) or moderate (CYP3A4/5) potential for drug-drug interactions. The potential for autoinhibition was low.Overall, GNE-617 exhibited acceptable preclinical properties and projected human PK and dose estimates.