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.
|Translated title of the contribution||Entwicklung von Matrix Metalloproteinase-13 Inhibitoren – Eine Studie zur Untersuchung der Struktur-Wirkbeziehung der Inhibitoren|
|Number of pages||11|
|Journal||Bioorganic & Medicinal Chemistry|
|Publication status||Published - 15 Aug 2018|
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