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Delamanid (formerly also known as OPC-67683; Deltyba) is a new neneration and potent drug that acts as a mycobacterial cell wall synthesis inhibitor for the treatment of multi-drug-resistant tuberculosis. It inhibits the synthesisi of mucolic acids, cruciala component of the cell wall of the Mycobacterium tuberculosis complex. Delamanid was approved in the EU. Delamanid is insoluble in water and its activity was proven in several in vitro and in vivo studies. Its bactericidal activity was demonstrated in individuals with drug-susceptible and drug-resistant tuberculosis (MDR- and XDR-TB).
Physicochemical Properties
| Molecular Formula | C25H25F3N4O6 |
| Molecular Weight | 534.4844 |
| Exact Mass | 534.172 |
| Elemental Analysis | C, 56.18; H, 4.71; F, 10.66; N, 10.48; O, 17.96 |
| CAS # | 681492-22-8 |
| Related CAS # | Delamanid-d4 |
| PubChem CID | 6480466 |
| Appearance | Off-white to yellow solid powder |
| Density | 1.5±0.1 g/cm3 |
| Boiling Point | 653.7±65.0 °C at 760 mmHg |
| Flash Point | 349.1±34.3 °C |
| Vapour Pressure | 0.0±2.0 mmHg at 25°C |
| Index of Refraction | 1.611 |
| LogP | 4.75 |
| Hydrogen Bond Donor Count | 0 |
| Hydrogen Bond Acceptor Count | 11 |
| Rotatable Bond Count | 7 |
| Heavy Atom Count | 38 |
| Complexity | 795 |
| Defined Atom Stereocenter Count | 1 |
| SMILES | FC(OC1C([H])=C([H])C(=C([H])C=1[H])OC1([H])C([H])([H])C([H])([H])N(C2C([H])=C([H])C(=C([H])C=2[H])OC([H])([H])[C@@]2(C([H])([H])[H])C([H])([H])N3C([H])=C([N+](=O)[O-])N=C3O2)C([H])([H])C1([H])[H])(F)F |
| InChi Key | XDAOLTSRNUSPPH-XMMPIXPASA-N |
| InChi Code | InChI=1S/C25H25F3N4O6/c1-24(15-31-14-22(32(33)34)29-23(31)38-24)16-35-18-4-2-17(3-5-18)30-12-10-20(11-13-30)36-19-6-8-21(9-7-19)37-25(26,27)28/h2-9,14,20H,10-13,15-16H2,1H3/t24-/m1/s1 |
| Chemical Name | (2R)-2-Methyl-6-nitro-2-[(4-{4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl}phenoxy)methyl]-2,3-dihydroimidazo[2,1-b][1,3]oxazole |
| Synonyms | OPC-67683; OPC 67683; OPC67683; trade name Deltyba |
| 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
| ln Vitro |
Mycobacterium tuberculosis complex's cell wall is made up primarily of mucolic acids, which are inhibited by delamanid[1]. When it comes to M. tuberculosis strains that are both drug-susceptible and drug-resistant, delamanid exhibits more potent antibacterial activity[2]. The coadministration of delamanid results in approximately 25% higher ethambutol AUCτ and Cmax values; however, delamanid does not affect the exposure to pyrazinamide, rifampin, or isoniazid[3]. |
| ln Vivo | In a mouse model of VL, delamanid (oral administration; 30 mg/kg; 5 days) causes sterile cures[4]. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Following a single oral dose administration of 100 mg delamanid, the peak plasma concentration was 135 ng/mL. Steady-state concentration is reached after 10-14 days. Delamanid plasma exposure increases less than proportionally with increasing dose. In animal models (dog, rat, mouse), the oral bioavailability of delamanid was reported to be 35%–60%. The absolute oral bioavailability in humans is estimated to range from 25 to 47%. Oral bioavailability in humans is enhanced when administered with a standard meal, by about 2.7 fold compared to fasting conditions because delamanid exhibits poor water solubility. Delamanid is excreted primarily in the stool, with less than 5% excretion in the urine. The apparent volume of distribution (Vz/F) is 2,100 L. Pharmacokinetic data in animals have shown excretion of delamanid and/or its metabolites into breast milk. In lactating rats, the Cmax for delamanid in breast milk was 4-fold higher than that of the blood. Metabolism / Metabolites Delamanid predominantly undergoes metabolism by albumin and to a lesser extent, CYP3A4.. The metabolism of delamanid may also be mediated by hepatic CYP1A1, CYP2D6, and CYP2E1 to a lesser extent [31966]. Four major metabolites (M1–M4) have been identified in plasma in patients receiving delamanid where M1 and M3 accounts for 13%–18% of the total plasma exposure in humans. While they do not retain significant pharmacological activity, they may still contribute to QT prolongation. This is especially true for the main metabolite of delamanid, M1 (DM-6705). Delamanid is predominantly metabolized by serum albumin to form M1 (DM-6705) via hydrolytic cleavage of the 6-nitro-2,3-dihydroimidazo[2,1-b] oxazole moiety. The formation of this major metabolite is suggested to be a crucial starting point in the metabolic pathway of delamanid. M1 (DM-6705) can be further catalyzed by three pathways. In the first metabolic pathway, DM-6705 undergoes hydroxylation of the oxazole moiety to form M2 ((4RS,5S)-DM-6720), followed by CYP3A4-mediated oxidation of hydroxyl group and tautomerization of oxazole to an imino-ketone metabolite, M3 ((S)-DM-6718). The second metabolic pathway involves the hydrolysis and deamination of the oxazole amine to form M4 (DM-6704) followed by hydroxylation to M6 ((4R,5S)-DM-6721) and M7 ((4S,5S)-DM-6722) and oxidation of oxazole to another ketone metabolite, M8 ((S)-DM-6717). The third pathway involves the hydrolytic cleavage of the oxazole ring to form M5 (DM-6706). Biological Half-Life The half life ranges from 30 to 38 hours. |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Delamanid is not approved for marketing in the United States by the U.S. Food and Drug Administration, but is available in other countries. No information is available on the clinical use of delamanid during breastfeeding. Preliminary evidence indicates that delamanid and its active metabolite are present in milk at low levels. Delamanid is usually given with several other drugs for resistant tuberculosis, so the clinical importance of these small amounts is unclear. ◉ 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 Delamanid highly binds to all plasma proteins with a binding to total proteins of ≥99.5%. |
| References |
[1]. Delamanid (OPC-67683) for treatment of multi-drug-resistant tuberculosis. Expert Rev Anti Infect Ther. 2015 Mar;13(3):305-15. [2]. Delamanid: A new armor in combating drug-resistant tuberculosis. J Pharmacol Pharmacother. 2014 Jul;5(3):222-4 [3]. Delamanid Coadministered with Antiretroviral Drugs or Antituberculosis Drugs Shows No Clinically Relevant Drug-Drug Interactions in Healthy Subjects. Antimicrob Agents Chemother. 2016 Sep 23;60(10):5976-85. [4]. The anti-tubercular drug delamanid as a potential oral treatment for visceral leishmaniasis. Elife. 2016 May 24;5. |
| Additional Infomation |
Delamanid is a member of piperidines. Delamanid is an anti-tuberculosis agent derived from the nitro-dihydro-imidazooxazole class of compounds that inhibits mycolic acid synthesis of bacterial cell wall. It is used in the treatment of multidrug-resistant and extensively drug-resistant tuberculosis (TB) in a combination regimen. Emergence of multidrug-resistant and extensively drug-resistant tuberculosis creates clinical challenges for patients, as the disease is associated with a higher mortality rate and insufficient therapeutic response to standardized antituberculosis treatments as [DB00951] and [DB01045]. Multidrug-resistant tuberculosis may also require more than 2 years of chemotherapy and second-line therapies with narrow therapeutic index. In a clinical study involving patients with pulmonary multidrug-resistant tuberculosis or extensively drug-resistant tuberculosis, treatment of delamanid in combination with WHO-recommended optimised background treatment regimen was associated with improved treatment outcomes and reduced mortality rate. Spontaneous resistance to delamanid was observed during treatment, where mutation in one of the 5 F420 coenzymes responsible for bioactivation of delamanid contributes to this effect. Delamanid is approved by the EMA and is marketed under the trade name Deltyba as oral tablets. It is marketed by Otsuka Pharmaceutical Co., Ltd (Tokyo, Japan). Delamanid is a nitro-dihydro-imidazooxazole derivative, with antimycobacterial activity. Upon oral administration, delamanid, a prodrug, is activated via the mycobacterial F420 coenzyme system to form a reactive intermediate metabolite that inhibits the synthesis of the mycobacterial cell wall components methoxy-mycolic and keto-mycolic acid. This leads to the depletion of these cell wall components and destruction of mycobacteria. Drug Indication Indicated for use as part of an appropriate combination regimen for pulmonary multi-drug resistant tuberculosis (MDR-TB) in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability. Deltyba is indicated for use as part of an appropriate combination regimen for pulmonary multi-drug resistant tuberculosis (MDR-TB) in adults, adolescents, children and infants with a body weight of at least 10 kg when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability (see sections 4. 2, 4. 4 and 5. 1). Consideration should be given to official guidance on the appropriate use of antibacterial agents. Treatment of multi-drug-resistant tuberculosis Mechanism of Action Delamanid is a prodrug that requires biotransformation via via the mycobacterial F420 coenzyme system, including the deazaflavin dependent nitroreductase (Rv3547), to mediate its antimycobacterial activity against both growing and nongrowing mycobacteria. Mutations in one of five coenzyme F420 genes, _fgd, Rv3547, fbiA, fbiB, and fbiC_ has been proposed as the mechanism of resistance to delamanid. Upon activation, the radical intermediate formed between delamanid and desnitro-imidazooxazole derivative is thought to mediate antimycobacterial actions via inhibition of methoxy-mycolic and keto-mycolic acid synthesis, leading to depletion of mycobacterial cell wall components and destruction of the mycobacteria. Nitroimidazooxazole derivative is thought to generate reactive nitrogen species, including nitrogen oxide (NO). However unlike isoniazid, delamanid does not alpha-mycolic acid. Pharmacodynamics The minimum inhibitory concentrations (MIC) of delamanid against _Mycobacterium tuberculosis_ isolates ranges from 0.006 to 0.024 g/mL. Among non-tuberculosis mycobacteria, delamanid has _in vitro_ activity against _M. kansasii_ and _M. bovis_. Delamanid has no in vitro activity against Gram negative or positive bacterial species and does not display cross-resistance to other anti-tuberculosis drugs. In murine models of chronic tuberculosis, the reduction of _M. tuberculosis_ colony counts by delamanid was demonstrated in a dose-dependent manner. Repeated dosing of delamanid may cause QTc-prolongation via inhibition of cardiac potassium channel (hERG channel), and this effect is mostly contributed by the main metabolite of delamanid, DM-6705. Animal studies indicate that delamanid may attenuate vitamin K-dependent blood clotting, increase prothrombin time (PT), and activated partial thromboplastin time (APTT). |
Solubility Data
| Solubility (In Vitro) |
DMSO : ~100 mg/mL ( ~187.09 mM) Ethanol : ~2 mg/mL (~3.74 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (4.68 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: ≥ 2.08 mg/mL (3.89 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 20.8 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 (4.68 mM) (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8710 mL | 9.3549 mL | 18.7098 mL | |
| 5 mM | 0.3742 mL | 1.8710 mL | 3.7420 mL | |
| 10 mM | 0.1871 mL | 0.9355 mL | 1.8710 mL |