Doravirine

MK-1439 exhibits greater than 10,000-fold selectivity with respect to the cellular DNA polymerases α, ß, and γ with IC50s of >100 μM. In the screen with more than 110 protein targets including enzymes, transporters, ion channels, and receptor, MK-1439 shows an IC50 of greater than 10 μM against all targets except 5-HT2ß, where an IC50 of 2.5 μM is noted in a ligand binding assay. However, the 5-HT2ß activity is not observed in a functional cell-based assay monitoring the accumulation of inositol-1-phosphate. Therefore, the binding activity does not appear to translate into a 5-HT2ß functional response. MK-1439 does not display cytotoxicity in activated CD4+ T cells, PBMCs, monocytes, macrophages proliferating transformed cell lines, such as MT4, SupT1, and HL60 cell lines at concentrations of up to 100 μM^[1].

In rats dosed IV at 1 mpk (60%PEG200), the clearance (CL) of MK-1439 is 5.4 mL/min/kg and the half time is 4.4 hr. Its volume of distribution (Vd) is 2.3 L/kg. The oral bioavailability of MK-1439 is 57% (doesed PO at 5 mpk). In dogs dosed IV at 0.5 mpk, the CL of MK-1439 is 0.36 mL/min/kg and half-time is 37 hr. The oral bioavailability of MK-1439 is 52% (doesed PO at 1 mpk). Overall, The pharmacokinetic profile of MK-1439 in preclinical species is favorable^[2].