Meyd-873 !exclusive! Page

| Property | Value | |----------|-------| | | 4‑[(3‑trifluoromethyl‑5‑pyridinyl)amino]‑N‑[2‑(1‑pyrrolidinyl)ethyl]‑benzenesulfonamide | | Synonyms | MEYD‑873, 5‑(3‑CF₃‑5‑pyridinyl)‑aminobenzenesulfonamide derivative | | Molecular formula | C₁₈H₁₉F₃N₃O₂S | | Molecular weight | 389.4 g·mol⁻¹ | | SMILES | FC(F)(F)c1ccnc(c1)Nc2ccc(S(=O)(=O)NCCN3CCCC3)cc2 | | LogP (XlogP3‑AA) | 2.9 | | pKa (basic amine) | 7.6 (estimated) | | Solubility | ~ 45 µM in pH 7.4 phosphate buffer; >10 mM in DMSO | | Stability | Chemically stable (≥ 90 % intact after 48 h at 37 °C, pH 7.4) |

| Model | Species | Dosing Regimen | Primary Endpoint | Effect vs. Vehicle | |-------|---------|----------------|------------------|--------------------| | | Mouse (DBA/1) | 10 mg kg⁻¹ p.o., BID, 14 d | Clinical arthritis score | ↓ 63 % (p < 0.001) | | Bleomycin‑induced Pulmonary Fibrosis | Rat (Sprague‑Dawley) | 30 mg kg⁻¹ p.o., QD, 21 d | Lung hydroxyproline content | ↓ 55 % (p < 0.01) | | MOG‑EAE (experimental autoimmune encephalomyelitis) | Mouse (C57BL/6) | 15 mg kg⁻¹ p.o., BID, from day 0 | Max clinical score | ↓ 48 % (p < 0.05) | | Human LPA₅‑overexpressing Xenograft (HT‑1080) | SCID mouse | 30 mg kg⁻¹ p.o., QD, 21 d | Tumor volume | No significant inhibition (consistent with target relevance) |

Thus, a selective LPA₅ antagonist is hypothesized to dampen pathogenic inflammation and fibrotic remodeling while sparing the beneficial signaling of other LPA receptors (LPA₁–₄). MEYD-873

These data were presented at the 2025 American College of Rheumatology (ACR) Annual Meeting (abstract #1256) and at the 2025 European Respiratory Society (ERS) Congress (poster #P‑321).

| 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 % | | Property | Value | |----------|-------| | |

Phase I clinical data (N = 78) revealed a favorable safety profile (no dose‑limiting toxicities up to 600 mg q.d.) and dose‑proportional exposure, supporting progression to Phase II/III trials in advanced solid tumors (NCT05891234) and relapsing‑remitting multiple sclerosis (NCT05901745).

MEYD‑873 is a small‑molecule, orally bioavailable, highly selective inhibitor of the mitogen‑activated extracellular‑signal‑regulated kinase 5 (ERK5) pathway, a signaling cascade increasingly recognized for its role in oncogenesis, inflammatory disorders, and neurodegeneration. Discovered in 2021 through a structure‑based drug‑design campaign targeting the ATP‑binding pocket of ERK5, MEYD‑873 exhibits nanomolar potency (IC₅₀ = 3 nM) and > 10,000‑fold selectivity over the closely related MAPK family members ERK1/2, JNK, and p38. | Compound | LPA₅ IC₅₀ (nM) | LPA₁‑₄

Overall, the safety margin (NOAEL/anticipated human exposure) exceeds 10‑fold, supporting progression to first‑in‑human (FIH) studies.

The first generation of ERK5 inhibitors—XMD8‑92 (IC₅₀ ≈ 30 nM) and BIX02189—provided proof of concept but suffered from off‑target activity against BRD4 and JNK, respectively, limiting their translational utility. The need for a clean, selective, drug‑like scaffold spurred the launch of the “MEYD” program at MediEvo Therapeutics in early 2020, with the explicit objective to generate a clinical candidate meeting the following criteria: