MMP13-IN-3 (Synonyms: MMP13-IN-3)

MMP13-IN-3 is a potent, selective, and orally active MMP-13 inhibitor (IC50=1 nM[1]) for the potential treatment of osteoarthritis[2]. MMP13-IN-3 is >1000 selective over other MMPs[1].

MMP13-IN-3 (Compound 15) is potent in a full-length MMP-13 collagen degradation assay (11 nM) and is able to inhibit degradation of bovine nasal cartilage with an IC50 of 31 nM. MMP13-IN-3 inhibits MMP-2, MMP-9, MMP-10 and MMP-14 with IC50s of 18, 8.9, 16 and 8.3 μM, respectively[1].

When dosed orally at 10 mg/kg or i.v. 1 mg/kg, MMP13-IN-3 (Compound 15) reaches micromolar plasma levels (AUC=1109±64 nM h/mL), displays modest clearance (CL=34 mL/min/kg), and shows acceptable bioavailability (39%). The Vss is quite low at 0.26 mL/mi/kg rat pharmacokinetic profile. MMP13-IN-3 has short terminal elimination half-life (t1/2=0.47 h for rat (1 mg/kg, i.v.) and rat (10 mg/kg, orally), respectively)[1].

[1]. Taylor SJ, et al. Fragment-based discovery of indole inhibitors of matrix metalloproteinase-13. J Med Chem. 2011 Dec 8;54(23):8174-87.
[2]. Ruminski PG, et al. Discovery of N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide. A Highly Selective and Orally Bioavailable Matrix Metalloproteinase-13 Inhibitor for the Potential Treatment of Osteoarthritis. J Med Chem. 2016 Jan 14;59(1):313-27.