Development of matrix metalloproteinase-13 inhibitors – A structure activity/structure-property relationship study

Rita Fürst, Jun Yong Choi, Anna M. Knapinska, Lyndsay Smith, Michael D. Cameron, Claudia Ruiz, Gregg B. Fields, William R. Roush

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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 contributionEntwicklung von Matrix Metalloproteinase-13 Inhibitoren – Eine Studie zur Untersuchung der Struktur-Wirkbeziehung der Inhibitoren
Original languageEnglish
Number of pages11
JournalBioorganic & Medicinal Chemistry
Issue number18
Publication statusPublished - 15 Aug 2018

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