Doravirine (formerly known as MK-1439 and DOR; trade name: Pifeltro) is a novel human immunodeficiency type 1 virus (HIV-1) nonnucleoside reverse transcriptase inhibitor (NNRTI) that is approved in August 2018 to treat HIV-1 infection in adult patients. Doravirine exhibits potent antiviral activity against wild-type virus and K103N, Y181C, and K103N/Y181C mutant viruses, with 50% inhibitory concentrations (IC50s) of 12, 21, 31, and 33 nM, respectively, when measured in 100% normal human serum (NHS). Selectivity and cytotoxicity studies confirmed that MK-1439 is a highly specific NNRTI with minimum off-target activities. In the presence of 50% normal human serum (NHS), MK-1439 showed excellent potency in suppressing the replication of WT virus, with a 95% effective concentration (EC95) of 20 nM, as well as K103N, Y181C, and K103N/Y181C mutant viruses with EC95 of 43, 27, and 55 nM, respectively. MK-1439 exhibited similar antiviral activities against 10 different HIV-1 subtype viruses (a total of 93 viruses). In addition, the susceptibility of a broader array of clinical NNRTI-associated mutant viruses (a total of 96 viruses) to MK-1439 and other benchmark NNRTIs was investigated.

Physicochemical Properties

Molecular Formula	C17H11CLF3N5O3
Molecular Weight	425.752
Exact Mass	425.05
Elemental Analysis	C, 47.96; H, 2.60; Cl, 8.33; F, 13.39; N, 16.45; O, 11.27
CAS #	1338225-97-0
Related CAS #	1338225-97-0
PubChem CID	58460047
Appearance	White to off-white solid powder
Density	1.6±0.1 g/cm3
Index of Refraction	1.631
LogP	3.01
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	8
Rotatable Bond Count	4
Heavy Atom Count	29
Complexity	860
Defined Atom Stereocenter Count	0
SMILES	N#CC1=CC(OC2=C(C(F)(F)F)C=CN(CC(N3C)=NNC3=O)C2=O)=CC(Cl)=C1
InChi Key	ZIAOVIPSKUPPQW-UHFFFAOYSA-N
InChi Code	InChI=1S/C17H11ClF3N5O3/c1-25-13(23-24-16(25)28)8-26-3-2-12(17(19,20)21)14(15(26)27)29-11-5-9(7-22)4-10(18)6-11/h2-6H,8H2,1H3,(H,24,28)
Chemical Name	3-Chloro-5-((1-((4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxy)benzonitrile
Synonyms	MK 1439; MK-1439; MK1439
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets	wild type reverse transcriptase(IC50= 4.5 nM);K103N reverse transcriptase(IC50= 5.5 nM);Y181C reverse transcriptase(IC50= 6.1 nM)
ln Vitro	Doravirine is a highly specific nonnucleoside reverse transcriptase inhibitor with very little off-target activity, according to studies on selectivity and cytotoxicity. Doravirine exhibits remarkable efficacy in inhibiting the replication of WT virus, with a 95% effective concentration (EC95) of 20 nM, and mutant viruses K103N, Y181C, and K103N/Y181C, with EC9595 of 43, 27, and 55 nM, respectively, when 50% normal human serum (NHS) is present. Comparable antiviral effects of doravirine have been observed against 93 viruses, representing 10 distinct HIV-1 subtype viruses[1].
ln Vivo	When 50 mg of doravirine is administered along with a high-fat meal, there is no change in Cmax but there are modest increases in AUC time zero to infinity and C24 h[2].
ADME/Pharmacokinetics	Absorption, Distribution and Excretion The absolute bioavailability of doravirine is 64% with a Tmax of 2 hours. Following oral [14C]doravirine administration, all of the administered dose was recovered and the agent is considered to be well absorbed. Moreover, its co-administration with food did not greatly alter doravirine's pharmacokinetic profile during clinical studies. The primary route of elimination for doravirine is via cytochrome P450 3A4/5 metabolism. Only 6% of an administered dose is recovered in the urine unchanged, with even less unchanged drug found in the feces. The steady-state volume of distribution of doravirine following intravenous administration is 60.5 L. The oral and renal clearances of doravirine are 106 ml/min and 9.3 ml/min, respectively. Metabolism / Metabolites Following absorption, unchanged parent drug is the major circulating component in plasma. Its M9 metabolite - a product of cytochrome P450 3A4/5 mediated oxidative metabolism - is the most abundant doravirine metabolite in the circulation. Biological Half-Life The elimination half-life determined of doravirine is 15 hours.
Toxicity/Toxicokinetics	Hepatotoxicity Serum aminotransferase elevations were reported in 13% of patients on doravirine therapy, but elevations above 5 times the upper limit of normal were uncommon, occurring in 1% or less of patients. The rate of serum aminotransferase elevations during doravirine therapy was higher in patients who were coinfected with hepatitis B or C, but the abnormalities were rarely severe. Doravirine has been in clinical use for a short time only, but unlike many other nonnucleoside reverse transcriptase inhibitors, doravirine has yet to be linked to reported instances of clinically apparent liver injury. Likelihood score: E* (suspected but unproven cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No published information is available on the use of doravirine during breastfeeding. An alternate drug may be preferred. Achieving and maintaining viral suppression with antiretroviral therapy decreases breastfeeding transmission risk to less than 1%, but not zero. Individuals with HIV who are on antiretroviral therapy with a sustained undetectable viral load and who choose to breastfeed should be supported in this decision. If a viral load is not suppressed, banked pasteurized donor milk or formula is recommended. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding Doravirine is approximately 76% protein-bound in plasma.
References	[1]. In vitro characterization of MK-1439, a novel HIV-1 nonnucleoside reverse transcriptase inhibitor. Antimicrob Agents Chemother. 2014;58(3):1652-63. [2]. Safety, tolerability and pharmacokinetics of doravirine, a novel HIV non-nucleoside reverse transcriptase inhibitor, after single and multiple doses in healthy subjects. Antivir Ther. 2015;20(4):397-405. [3]. Antimicrob Agents Chemother.2016 Mar 25;60(4):2241-7.
Additional Infomation	Doravirine (brand name: Pifeltro) is a prescription medicine approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV infection in adults and children who weigh at least 77 lb (35 kg) and who meet certain requirements, as determined by a health care provider. Doravirine is always used in combination with other HIV medicines. Doravirine is an HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) intended to be administered in combination with other antiretroviral medicines. Doravirine is available by itself or as a combination product of doravirine (100 mg), lamivudine (300 mg), and tenofovir disoproxil fumarate (300 mg). Doravirine is formally indicated for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment experience, further expanding the possibility and choice of therapeutic treatments available for the management of HIV-1 infection. Doravirine is a Human Immunodeficiency Virus 1 Non-Nucleoside Analog Reverse Transcriptase Inhibitor. The mechanism of action of doravirine is as a Non-Nucleoside Reverse Transcriptase Inhibitor. Doravirine is a nonnucleoside reverse transcriptase inhibitor used in combination with other antiretroviral agents in the therapy of human immunodeficiency virus (HIV) infection. Doravirine is associated with a low rate of transient serum aminotransferase elevations during therapy but has not been implicated in cases of clinically apparent acute liver injury. Doravirine is a pyridinone non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1), that is used to treat HIV infection. Upon oral administration, doravirine non-competitively inhibits HIV-1 reverse transcriptase (RT), thereby inhibiting HIV-1 viral replication. See also: ... View More ... Drug Indication Doravirine is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment history. It is also indicated to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to doravirine. FDA Label Pifeltro is indicated, in combination with other antiretroviral medicinal products, for the treatment of adults, and adolescents aged 12 years and older weighing at least 35 kg infected with HIV 1 without past or present evidence of resistance to the NNRTI class. Treatment of human immunodeficiency virus type 1 (HIV-1) infection Mechanism of Action Doravirine is a pyridinone non-nucleoside reverse transcriptase inhibitor of HIV-1. Reverse transcriptase is the enzyme with which HIV generates complementary DNA (cDNA) to its RNA genome - this cDNA is then inserted into the host cell genome, where it can be transcribed into viral RNA for the purposes of replication. Doravirine inhibits HIV-1 replication by non-competitively inhibiting HIV-1 reverse transcriptase. Doravirine does not, however, inhibit the human cellular DNA polymerases α, ß, and mitochondrial DNA polymerase γ. Pharmacodynamics In a clinical phase 2 trial evaluating a dose range of 0.25-2x the recommended dose of doravirine (in combination with emtricitabine/tenofovir) in HIV-1 infected subjects with no antiretroviral treatment history, no exposure-response relationship for efficacy was identified for doravirine. Furthermore, at a dose of 1200 mg, which provides approximately 4 times the peak concentration observed following the recommended dose, doravirine does not prolong the QT interval to any clinically relevant extent.

Solubility Data

Solubility (In Vitro)

DMSO : 85 ~100 mg/mL (199.64~234.88 mM)

Solubility (In Vivo)

Solubility in Formulation 1: 2.5 mg/mL (5.87 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.87 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 3: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: 2.5 mg/mL (5.87 mM)  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.3488 mL	11.7440 mL	23.4880 mL
	5 mM	0.4698 mL	2.3488 mL	4.6976 mL
	10 mM	0.2349 mL	1.1744 mL	2.3488 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.