All assays were performed at Meyden’s CRO network using standard radioligand competition (¹⁴C‑LPA) and patch‑clamp for hERG. | Parameter | Value (mouse) | Value (rat) | Value (dog) | |-----------|---------------|-------------|-------------| | In‑vitro potency (LPA₅ functional antagonism, Ca²⁺ flux) | 42 nM | 48 nM | 55 nM | | Selectivity (≥ 100‑fold vs. LPA₁‑₄, S1P₁‑₅) | — | — | — | | Oral bioavailability | 68 % (p.o., 10 mg kg⁻¹) | 62 % | 55 % | | C_max (μM) at 30 mg kg⁻¹ p.o. | 4.2 | 3.8 | 3.1 | | t₁/₂ (h) | 3.5 | 4.2 | 5.0 | | Plasma protein binding | 92 % (mouse) | 90 % (rat) | 88 % (dog) | | Brain penetration (K_p,uu) | 0.12 | 0.09 | 0.07 | | Key metabolites | N‑desethyl MEYD‑873 (inactive) | N‑desethyl (inactive) | Same |
The compound exhibits low CNS exposure, consistent with the intended peripheral therapeutic window. | Model | Species | Dosing Regimen | Primary Endpoint | Effect vs. Vehicle | |-------|---------|----------------|------------------|--------------------| | Collagen‑Induced Arthritis (CIA) | 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) | MEYD-873
*Freedom‑to‑operate analyses indicate no overlapping claims with existing LPA antagonists (e.g., SAR‑20347, a LPA₁/₃ inhibitor All assays were performed at Meyden’s CRO network