A structure-activity/structure-property relationship study based on the physicochemical as well as in vitro pharmacokinetic properties of a first generation matrix metalloproteinase (MMP)-13 inhibitor (2) was undertaken. After systematic variation of inhibitor 2, compound 31 was identified which exhibited microsomal half-life higher than 20 min, kinetic solubility higher than 20 μM, and a permeability coefficient greater than 20 x 10-6 cm/s. Compound 31 also showed excellent in vivo PK properties after IV dosing (Cmax = 56.8 μM, T1/2 (plasma) = 3.0 h, Cl = 0.23 mL/min/kg) and thus is a suitable candidate for in vivo efficacy studies in an OA animal model.
Fürst, R., Choi, J. Y., Knapinska, A. M., Smith, L., Cameron, M. D., Ruiz, C., ... Roush, W. R. (2018). Development of matrix metalloproteinase-13 inhibitors – A structure activity/structure-property relationship study. Bioorganic & Medicinal Chemistry, 26(18). https://doi.org/10.1016/j.bmc.2018.08.020