-Elexacaftor ((R)-VX-445) Chemical Structure.png)
On Dec. 20, 2024, Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) announced the U.S. Food and Drug Administration (FDA) has approved the expanded use of TRIKAFTA® (elexacaftor/tezacaftor/ivacaftor and ivacaftor) for the treatment of people with cystic fibrosis (CF) ages 2 and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or a mutation that is responsive to TRIKAFTA based on clinical and/or in vitro data. In addition, safety information on liver injury and liver failure has been updated from warnings and precautions to a boxed warning. With this approval, 94 additional non-F508del CFTR mutations have been added to the TRIKAFTA label, and approximately 300 additional people with CF in the U.S. are now eligible for a medicine to treat the underlying cause of their disease for the first time. “Since its first approval in 2019, TRIKAFTA has had a transformative impact on tens of thousands of people living with cystic fibrosis,” said Carmen Bozic, M.D., Executive Vice President, Global Medicines Development and Medical Affairs, and Chief Medical Officer, Vertex. “With this approval, even more patients may be able to benefit from a medicine that treats the underlying cause of their disease, and we look forward to continuing the work to extend the approvals and availability of our medicines to patients around the world.”
Physicochemical Properties
| Molecular Formula | C26H34F3N7O4S |
| Molecular Weight | 597.652874469757 |
| Exact Mass | 597.234 |
| Elemental Analysis | C, 52.25 H, 5.73 F, 9.54 N, 16.41 O, 10.71 S, 5.36 |
| CAS # | 2229860-99-3 |
| Related CAS # | Elexacaftor;2216712-66-0 |
| PubChem CID | 134587287 |
| Appearance | White to light yellow solid powder |
| LogP | 4.9 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 11 |
| Rotatable Bond Count | 8 |
| Heavy Atom Count | 41 |
| Complexity | 1050 |
| Defined Atom Stereocenter Count | 1 |
| SMILES | S(C1=CN(C)N=C1C)(NC(C1=CC=C(N2C=CC(=N2)OCC(C)(C)C(F)(F)F)N=C1N1C[C@H](C)CC1(C)C)=O)(=O)=O |
| InChi Key | MVRHVFSOIWFBTE-MRXNPFEDSA-N |
| InChi Code | InChI=1S/C26H34F3N7O4S/c1-16-12-25(5,6)35(13-16)22-18(23(37)33-41(38,39)19-14-34(7)31-17(19)2)8-9-20(30-22)36-11-10-21(32-36)40-15-24(3,4)26(27,28)29/h8-11,14,16H,12-13,15H2,1-7H3,(H,33,37)/t16-/m1/s1 |
| Chemical Name | N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)pyrazol-1-yl]-2-[(4R)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide |
| Synonyms | (R)-Elexacaftor; 2229860-99-3; (R)-N-((1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl)-6-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl)-2-(2,2,4-trimethylpyrrolidin-1-yl)nicotinamide; VX-445 R enantiomer; SCHEMBL20239741; MVRHVFSOIWFBTE-MRXNPFEDSA-N; |
| 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 | CFTR/cystic fibrosis transmembrane conductance regulator |
| ln Vitro | In vitro, VX-445-tezacaftor-ivacaftor significantly improved Phe508del CFTR protein processing, trafficking, and chloride transport to a greater extent than any two of these agents in dual combination. [2] |
| ln Vivo | In patients with cystic fibrosis, VX-445–tezacaftor–ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. The treatment also resulted in an increased percentage of predicted FEV1 of up to 13.8 points in the Phe508del–MF group (P<0.001). In patients in the Phe508del–Phe508del group, who were already receiving tezacaftor–ivacaftor, the addition of VX-445 resulted in an 11.0-point increase in the percentage of predicted FEV1 (P<0.001). In both groups, there was a decrease in sweat chloride concentrations and improvement in the respiratory domain score on the Cystic Fibrosis Questionnaire–Revised. CONCLUSIONS: The use of VX-445–tezacaftor–ivacaftor to target Phe508del CFTR protein resulted in increased CFTR function in vitro and translated to improvements in patients with cystic fibrosis with one or two Phe508del alleles. This approach has the potential to treat the underlying cause of cystic fibrosis in approximately 90% of patients [2]. |
| References |
[1]. MODULATOR OF THE CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR , PHARMACEUTICAL COMPOSITIONS , METHODS OF TREATMENT , AND PROCESS FOR MAKING THE MODULATOR. US 20180162839 A1. [2]. VX-445-Tezacaftor-VX-770 in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. N Engl J Med. 2018 Oct 25;379(17):1612-1620. |
Solubility Data
| Solubility (In Vitro) | DMSO: 125 mg/mL (209.15 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.48 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (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 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 (3.48 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6732 mL | 8.3661 mL | 16.7322 mL | |
| 5 mM | 0.3346 mL | 1.6732 mL | 3.3464 mL | |
| 10 mM | 0.1673 mL | 0.8366 mL | 1.6732 mL |