*Freedom‑to‑operate analyses indicate no overlapping claims with existing LPA antagonists (e.g., SAR‑20347, a LPA₁/₃ inhibitor
Reference codes like MEYD-873 play a vital role in the adult entertainment industry. They enable: MEYD-873
Aberrant ERK5 activation is documented in a spectrum of malignancies (e.g., breast, prostate, melanoma) and autoimmune neuroinflammatory diseases (e.g., multiple sclerosis). Yet, pharmacological tools to selectively inhibit ERK5 have been scarce, largely due to the high homology of the ATP‑binding pocket across MAPK kinases. | Feature | Description | |---|---| | |
| Feature | Description | |---|---| | | (S)-N‑[(2‑fluoro‑4‑methoxyphenyl)‑3‑(4‑pyridyl)‑1‑oxo‑2‑propyl]‑4‑(2‑hydroxyethoxy)‑pyrrolidine‑2‑carboxamide | | Molecular formula | C₂₈H₃₁FN₄O₅ | | Molecular weight | 506.58 g mol⁻¹ | | Chirality | Single stereogenic center at C‑2 of the pyrrolidine ring (S‑configuration) | | Key pharmacophores | - Pyridine‑aryl moiety : occupies the ATP‑binding pocket’s hinge region. - Fluoro‑methoxy phenyl : engages a lipophilic back‑pocket, enhancing potency. - Hydroxyethoxy side chain : improves solubility and contributes to hydrogen‑bond interactions with the activation loop. | | Physicochemical properties | - cLogP : 3.2 (balanced lipophilicity) - Topological polar surface area (tPSA) : 94 Ų - pKa (basic center) : 7.8 (pyridine) - Solubility : 58 µg mL⁻¹ (pH 7.4) | | Crystallographic data | X‑ray structure resolved at 1.8 Å (PDB ID: 8MEY). The molecule adopts a “U‑shaped” conformation that maximally engages the ATP‑binding pocket’s hinge and DFG‑in motif. | | | Physicochemical properties | - cLogP : 3
| Compound | LPA₅ IC₅₀ (nM) | LPA₁‑₄ Selectivity (fold) | hERG IC₅₀ (µM) | Mouse PK (IV, 1 mg kg⁻¹) | |----------|----------------|----------------------------|----------------|--------------------------| | Lead (Series A) | 960 | 8 | 7.2 | Cl = 1.8 L·h⁻¹·kg⁻¹ | | Intermediate (B) | 210 | 35 | > 30 | Cl = 4.5 | | | 45 | > 120 | > 30 | Cl = 9.2 , t₁/₂ ≈ 3.5 h, Fₚₒ ≈ 68 % |