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

doi:https://doi.org/10.1016/j.bmc.2018.08.020

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

Institute of Organic Chemistry (6410)

Research output: Contribution to journal › Article › peer-review

Abstract

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
Original language	English
Number of pages	11
Journal	Bioorganic & Medicinal Chemistry
Volume	26
Issue number	18
DOIs	https://doi.org/10.1016/j.bmc.2018.08.020
Publication status	Published - 15 Aug 2018

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https://doi.org/10.1016/j.bmc.2018.08.020

Cite this

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title = "Development of matrix metalloproteinase-13 inhibitors – A structure activity/structure-property relationship study",

abstract = "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.",

author = "Rita F{\"u}rst and Choi, {Jun Yong} and Knapinska, {Anna M.} and Lyndsay Smith and Cameron, {Michael D.} and Claudia Ruiz and Fields, {Gregg B.} and Roush, {William R.}",

year = "2018",

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language = "English",

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T1 - Development of matrix metalloproteinase-13 inhibitors – A structure activity/structure-property relationship study

AU - Fürst, Rita

AU - Choi, Jun Yong

AU - Knapinska, Anna M.

AU - Smith, Lyndsay

AU - Cameron, Michael D.

AU - Ruiz, Claudia

AU - Fields, Gregg B.

AU - Roush, William R.

PY - 2018/8/15

Y1 - 2018/8/15

N2 - 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.

AB - 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.

U2 - https://doi.org/10.1016/j.bmc.2018.08.020

DO - https://doi.org/10.1016/j.bmc.2018.08.020

M3 - Article

SN - 0968-0896

VL - 26

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

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