Dagrocorat (also known as PF-00251802) is a novel and potent dissociated glucocorticoid receptor agonist with the potential usefulness as an anti-inflammatory agent. The dissociated agonists of the glucocorticoid receptor are a novel class of agents in clinical development for rheumatoid arthritis. PF-04171327 (fosdagrocorat) is a phosphate ester prodrug of PF-00251802 (dagrocorat), a selective high-affinity partial agonist of the glucocorticoid receptor, which is further metabolized to PF-04015475. PF-00251802 is a reversible inhibitor of several CYPs, but modeling has suggested no clinically relevant interaction. PF-00251802 and PF-04015475 are time-dependent inhibitors and inducers of CYP3A in vitro; PF-00251802 is also a time-dependent inhibitor of CYP2D6. Model-based prediction suggested the potential for weak inhibition of CYP3A in vivo. A clinical DDI study was conducted with midazolam, a sensitive CYP3A substrate. A phase 1 open-label, multiple-dose study evaluated the effect of PF-04171327 on midazolam pharmacokinetics and safety in 12 healthy volunteers. Administration of midazolam alone or concomitantly with PF-04171327 resulted in equivalent pharmacokinetic profiles (AUCinf , 21.17 vs 20.28 ng·h/mL, respectively), indicating that PF-04171327 had no net effect on CYP3A activity in vivo. These findings support the further development of PF-00251802 and PF-04171327 as potential treatments for patients with rheumatoid arthritis (NCT00987038).
Physicochemical Properties
| Molecular Formula | C29H29F3N2O2 |
| Molecular Weight | 494.547978162766 |
| Exact Mass | 494.218 |
| CAS # | 1044535-52-5 |
| Related CAS # | Dagrocorat hydrochloride;1044535-61-6 |
| PubChem CID | 24873449 |
| Appearance | White to off-white solid powder |
| LogP | 6.235 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 6 |
| Rotatable Bond Count | 4 |
| Heavy Atom Count | 36 |
| Complexity | 785 |
| Defined Atom Stereocenter Count | 3 |
| SMILES | CC1=C(C=CC=N1)NC(=O)C2=CC3=C(C=C2)[C@@]4(CC[C@@](C[C@H]4CC3)(C(F)(F)F)O)CC5=CC=CC=C5 |
| InChi Key | QJJBNCHSWFGXML-QPVYNBJUSA-N |
| InChi Code | InChI=1S/C29H29F3N2O2/c1-19-25(8-5-15-33-19)34-26(35)22-10-12-24-21(16-22)9-11-23-18-28(36,29(30,31)32)14-13-27(23,24)17-20-6-3-2-4-7-20/h2-8,10,12,15-16,23,36H,9,11,13-14,17-18H2,1H3,(H,34,35)/t23-,27-,28+/m1/s1 |
| Chemical Name | (4bR,7S,8aR)-4b-benzyl-7-hydroxy-N-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-2-carboxamide |
| Synonyms | PF-251802; PF 251802; PF251802; PF-00251802; PF 00251802; PF00251802; |
| 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 | Cytochrome P450 (CYP)3A breaks down dagrocorat into N-oxide metabolites. Reversible inhibitors of several CYPs, including CYP2D6 and CYP3A, include dagrocorat[1]. |
| References |
[1]. In Vitro and In Vivo Investigation of Potential for Complex CYP3A Interaction for PF-00251802 (Dagrocorat), a Novel Dissociated Agonist of the Glucocorticoid Receptor. Clin Pharmacol Drug Dev. 2018 Mar;7(3):244-255. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~250 mg/mL (~505.51 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 6.25 mg/mL (12.64 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 62.5 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: ≥ 6.25 mg/mL (12.64 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 62.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0220 mL | 10.1102 mL | 20.2204 mL | |
| 5 mM | 0.4044 mL | 2.0220 mL | 4.0441 mL | |
| 10 mM | 0.2022 mL | 1.0110 mL | 2.0220 mL |