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Tenofovir exalidex (formerly known as HDP-Tenofovir and CMX-157) is a novel and potent lipophilic / acyclic nucleoside phosphonate that is able to deliver high concentrations of the active antiviral agent tenofovir to target cells. Tenofovir exalidex results in decreased circulating levels, lowering systemic exposure and thereby reducing the potential for renal and bone side effects. Potential Advantages of Tenofovir exalidex over Increased efficacy by boosting bioavailability; Takes advantage of natural lipid uptake mechanisms; Decreased renal toxicity by reduced circulating TFV; 97-fold more active against HBV in vitro.
Physicochemical Properties
| Molecular Formula | C28H52N5O5P |
| Molecular Weight | 569.7278 |
| Exact Mass | 569.371 |
| Elemental Analysis | C, 59.03; H, 9.20; N, 12.29; O, 14.04; P, 5.44 |
| CAS # | 911208-73-6 |
| Related CAS # | 202138-50-9n(fumarate);206184-49-8 (hydrate);379270-37-8n(alafenamide);206184-49-8 (hydrate);1571075-19-8n(aspartate);201341-05-1 Tenofovir dsoproxil);1236287-04-9 (Tenofovirnmaleate);1392275-56-7 (Tenofovir alafenamide hemifumarate);379270-38-9n(Tenofovir alafenamide fumarate);1453166-76-1 (Tenofovir disoproxil phosphate);1637632-97-3n(Tenofovir disoproxil succinate) |
| PubChem CID | 23628250 |
| Appearance | White to off-white solid powder. |
| LogP | 7.442 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 9 |
| Rotatable Bond Count | 25 |
| Heavy Atom Count | 39 |
| Complexity | 650 |
| Defined Atom Stereocenter Count | 1 |
| SMILES | C(N1C=NC2C(=NC=NC1=2)N)[C@@H](C)OCP(O)(=O)OCCCOCCCCCCCCCCCCCCCC |
| InChi Key | BPPMYUZIZUESBY-MLEONAHRSA-N |
| InChi Code | InChI=1S/C28H52N5O5P/c1-3-4-5-6-7-8-9-10-11-12-13-14-15-16-18-36-19-17-20-38-39(34,35)24-37-25(2)21-33-23-32-26-27(29)30-22-31-28(26)33/h22-23,25H,3-21,24H2,1-2H3,(H,34,35)(H2,29,30,31)/t25-/m1/s1 |
| Chemical Name | 3-(hexadecyloxy)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate |
| Synonyms | Tenofovir exalidex; HDP-Tenofovir; Tenofovir; CMX-157; HDP-Tenofovir; CMX-157; 3-(Hexadecyloxy)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate; K7J545MEMA; 9-R-(2-(Phosphonomethoxy)propyl)adenine; CMX157; CMX 157 |
| 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 | HIV-1;HIV-2 |
| ln Vitro |
Tenofovir exalidex exhibits a consistent >300-fold increase in activity compared to Tenofovir against various viruses across multiple cell systems. Tenofovir exalidex is effective against MNR mutants, including those that don't react to any of the NRTIs that are on the market right now. CMX157's average EC50 in PBMCs was 2.6 nM (range, 0.2 to 7.2 nM) against a panel of 27 wild-type HIV-1 isolates representing group M subtypes A to G and group O. This is noteworthy[1]. Although cyclophilins are not known to bind to HBV polymerase or participate in DNA elongation, tenofovir exalidex works as a therapeutic by blocking HBV polymerase-mediated HBV DNA elongation. Tenofovir exalidex (direct-acting) and CRV431 (host-targeting) together have a combination effect on HBV DNA production that is more consistent with the two drugs acting on different stages of the HBV life cycle[3]. |
| ln Vivo | Oral administration of tenofovir exalidex (Sprague-Dawley rats) at doses of 10, 30, or 100 mg/kg/day to rats for seven days does not appear to be toxic[2]. Metovir exalidex (5–10 mg/kg; oral gavage; once daily for 16 days) reduces HBV DNA levels in the liver in a dose-dependent manner[3]. |
| Cell Assay | CMX157 is a lipid (1-0-hexadecyloxypropyl) conjugate of the acyclic nucleotide analog tenofovir (TFV) with activity against both wild-type and antiretroviral drug-resistant HIV strains, including multidrug nucleoside/nucleotide analog-resistant viruses. CMX157 was consistently >300-fold more active than tenofovir against multiple viruses in several different cell systems. CMX157 was active against all major subtypes of HIV-1 and HIV-2 in fresh human peripheral blood mononuclear cells (PBMCs) and against all HIV-1 strains evaluated in monocyte-derived macrophages, with 50% effective concentrations (EC(50)s) ranging between 0.20 and 7.2 nM. The lower CMX157 EC(50)s can be attributed to better cellular uptake of CMX157, resulting in higher intracellular levels of the active antiviral anabolite, TFV-diphosphate (TFV-PP), inside target cells. CMX157 produced >30-fold higher levels of TFV-PP in human PBMCs exposed to physiologically relevant concentrations of the compounds than did TFV. Unlike conventional prodrugs, including TFV disoproxil fumarate (Viread), CMX157 remains intact in plasma, facilitating uptake by target cells and decreasing relative systemic exposure to TFV. There was no detectable antagonism with CMX157 in combination with any marketed antiretroviral drug, and it possessed an excellent in vitro cytotoxicity profile. CMX157 is a promising clinical candidate to treat wild-type and antiretroviral drug-resistant HIV, including strains that fail to respond to all currently available nucleoside/nucleotide reverse transcriptase inhibitors[1]. |
| Animal Protocol |
Animal Model: transgenic mice that are female Tg05 transgenic mice for HBV (C57BL/6)[1] Dosage: 5 mg/kg, 10 mg/kg Administration: Oral gavage; daily for a period of 16 days Result: For low-dose (5 mg/kg/day) and high-dose (10 mg/kg/day), the reductions in HBV DNA were 55% and 97%, respectively. |
| References |
[1]. Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV. Antimicrob Agents Chemother. 2010;54(7):2901-2909. [2]. The cyclophilin inhibitor CRV431 inhibits liver HBV DNA and HBsAg in transgenic mice. PLoS One. 2019;14(6):e0217433. Published 2019 Jun 10. [3]. Evaluation of hexadecyloxypropyl-9-R-[2-(Phosphonomethoxy)propyl]- adenine, CMX157, as a potential treatment for human immunodeficiency virus type 1 and hepatitis B virus infections [published correction appears in Antimicrob Agents Chemother. 2007 Dec;51(12):4538]. Antimicrob Agents Chemother. 2007;51(10):3505-3509. |
| Additional Infomation | Tenofovir exalidex is under investigation in clinical trial NCT01080820 (A Safety, Tolerability and Pharmacokinetic Study of a Single Dose of CMX157 in Healthy Volunteers). |
Solubility Data
| Solubility (In Vitro) | DMSO : ~100 mg/mL (~175.52 mM） |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2 mg/mL (3.51 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 20.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7552 mL | 8.7761 mL | 17.5522 mL | |
| 5 mM | 0.3510 mL | 1.7552 mL | 3.5104 mL | |
| 10 mM | 0.1755 mL | 0.8776 mL | 1.7552 mL |