MK-4827 (Racemate)

MK-4827 Racemate is an excellent PARP1 inhibitor with IC₅₀ of 3.2 nM. IC50 & Target: IC50: 3.2 nM (PARP1)^[1] In Vitro: MK-4827 R-enantiomer Resolution of MK-4827 Racemate give compounds MK-4827 R-enantiomer and MK-4827 S-enantiomer, both showing excellent inhibition of PARP-1. The MK-4827 R-enantiomer has somewhat lower in vitro metabolic clearance than the MK-4827 S-enantiomer in rat liver microsomes, but MK-4827 S-enantiomer is more potent in cell based assays (PARylation EC₅₀, MK-4827 R-enantiomer=30 nM, MK-4827 S-enantiomer=4.0 nM; BRCA1-HeLa CC₅₀, MK-4827 R-enantiomer=470, MK-4827 S-enantiomer=34 nM). Given this improved potency and similar in vitro turnover in human liver microsomes (HLM Cl_int, MK-4827 R-enantiomer=4, MK-4827 S-enantiomer=3 μL/min/mgP), MK-4827 S-enantiomer (Niraparib) is focused on^[1]. In Vivo: As well as its moderate clearance in rat, MK-4827 S-enantiomer shows good bioavailability (65%) and a high volume of distribution (V_dss=6.9 L/kg), leading to a reasonably long terminal half-life (t_1/2=3.4 h)^[1].