Description

Doravirine, also referred to as MK-1439 or “DOR,” is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) currently in development for the treatment of patients with human immunodeficiency virus type 1 (HIV-1) infection in combination with other antiretroviral therapies[1]. Doravirine was discovered and developed by Merck. The drug was approved in 2018 by the USFDA for the treatment of HIV-1 in appropriate patients. The once-daily dosed drug,  like all NNRTIs, inhibits viral DNA synthesis by binding to an allosteric site located about 10 ? from the polymerase active site of the HIV-1 reverse transcriptase. Doravirine has demonstrated significant antiviral activity against a broad range of NNRTI-resistance-associated mutations that are increasingly found in treatment-naive patients while exhibiting an improved safety profile over existing standard-of-care regimens such as ritonavir, darunavir, and efavirenz.

Synthetic method

Many accounts related to the preparation of doravirine and related analogs have been published, and researchers at Merck have described a robust, kilogram-scale synthesis of the drug[2]. Strategically, this scale route was designed to proceed through substrates that would minimize the evolution of doravirine byproducts that arose from polymethylation and polycyanation, which were challenging to remove by methods other than chromatography. Toward this end, an iridium-catalyzed meta-borylation?oxidation protocol converted iodochlorobenzene 98 to phenol 99, which then participated in an S N Ar reaction with pyridine 100 to arrive at diaryl ether 101. Basic hydrolysis of 101 followed by recrystallization gave rise to 2-pyridinol 102 in 87% yield from 98. Next, introducing the nitrile using copper cyanide in NMP was introduced under relatively mild conditions. The authors note that keeping the temperature under 110 °C was critical for suppressing undesired bis-cyanation products. The iodide was chosen over the analogous bromide to help further ensure selectivity for the desired mononitrile product 103. Alkylation of 103 with 5- (chloromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (104) was possible under mild conditions to give 2-pyridone 105 in 81% yield after recrystallization. Although 104 is commercially available, reports of its preparation have also been previously published. Lastly, after screening various methylation conditions, 105 was treated with iodomethane and potassium carbonate in cool NMP, furnishing doravirine (IX) in 68% yield, with minimal over methylation products observed.

Pharmacokinetics

Doravirine is absorbed quickly after oral administration (e.g., reaching maximum plasma concentrations in a median of 1–4 h in healthy volunteers taking 30–750 mg once daily). Its bioavailability is not impacted to any clinically relevant extent when taken with food (either as a single-agent tablet or as the doravirine/lamivudine/tenofovir DF FDC tablet). Notably, in a single-dose study in healthy volunteers, doravirine, lamivudine, and tenofovir exposure after administration of the FDC tablet was comparable to when the individual drugs were co-administered at the FDC doses. Doravirine displays 76% plasma protein binding and, after intravenous administration, has a volume of distribution of 60.5 L at a steady state. Metabolism of doravirine occurs primarily via CYP3A enzymes. It is the major route of the drug’s elimination, with little of a dose being excreted unchanged via the urine (6%) or biliary/fecal routes (no values reported). Doravirine has an elimination half-life of 15 h, a mean apparent clearance of 106 mL/min, and a mean renal clearance of 9.3 mL/min[3].

References

[1]K. Yee. “Evaluation of Doravirine Pharmacokinetics When Switching from Efavirenz to Doravirine in Healthy Subjects.” Antimicrobial Agents and Chemotherapy 5 1 (2016).

[2]Andrew C. Flick. “Synthetic Approaches to New Drugs Approved during 2018.” Journal of Medicinal Chemistry 63 19 (2020): 10652–10704.

[3]Deeks, Emma D. “Doravirine: First Global Approval.” Drugs 78 15 (2018): 1643–1650.