Development of a putative Zn2+-chelating but highly selective MMP-13 inhibitor

Rita Fürst; Jun Yong Choi; Anna M. Knapinska; Michael D. Cameron; Claudia Ruiz; Amber Delmas; Mark S. Sundrud; Gregg B. Fields; William R. Roush

doi:10.1016/j.bmcl.2022.129014

Development of a putative Zn2+-chelating but highly selective MMP-13 inhibitor

Rita Fürst^*, Jun Yong Choi, Anna M. Knapinska, Michael D. Cameron, Claudia Ruiz, Amber Delmas, Mark S. Sundrud, Gregg B. Fields^*, William R. Roush^*

^*Corresponding author for this work

Institute of Organic Chemistry (6410)

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

Abstract

Starting from an already known MMP-13 inhibitor, 1, we pursued an SAR-approach focusing on optimizing interactions close to the Zn²⁺ binding site of the enzyme. We found the oxetane containing compound 32 (MMP-13 IC₅₀ = 42 nM), which exhibited complete inhibition of collagenolysis in in vitro studies and an excellent selectivity profile among the MMP family. Interestingly, docking studies propose that the oxetane ring in 32 is oriented towards the Zn²⁺ ion for chelating the metal ion. Chelating properties of MMP13-inhibitors are often connected with non-selectivity within the enzyme family. Compound 32 demonstrates a rare example where the selectivity can be explained via combinatorial effects of interactions within the S₁′ loop and a chelating effect of the oxetane moiety. Furthermore, in vivo pharmacokinetic studies were performed demonstrating a concentration of 1.97 μM of 32 within the synovial fluid of the rat knee joint, which makes the compound a promising lead compound for further optimization and development for osteoarthritis.

Original language	English
Article number	129014
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	76
DOIs	https://doi.org/10.1016/j.bmcl.2022.129014
Publication status	Published - 15 Nov 2022

Keywords

Collagenolysis inhibition
In vitro and in vivo pharmacokinetics
Matrix metalloproteinase 13
Oxetane containing inhibitors
Structure–activity relationship

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2022.129014

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title = "Development of a putative Zn2+-chelating but highly selective MMP-13 inhibitor",

abstract = "Starting from an already known MMP-13 inhibitor, 1, we pursued an SAR-approach focusing on optimizing interactions close to the Zn2+ binding site of the enzyme. We found the oxetane containing compound 32 (MMP-13 IC50 = 42 nM), which exhibited complete inhibition of collagenolysis in in vitro studies and an excellent selectivity profile among the MMP family. Interestingly, docking studies propose that the oxetane ring in 32 is oriented towards the Zn2+ ion for chelating the metal ion. Chelating properties of MMP13-inhibitors are often connected with non-selectivity within the enzyme family. Compound 32 demonstrates a rare example where the selectivity can be explained via combinatorial effects of interactions within the S1′ loop and a chelating effect of the oxetane moiety. Furthermore, in vivo pharmacokinetic studies were performed demonstrating a concentration of 1.97 μM of 32 within the synovial fluid of the rat knee joint, which makes the compound a promising lead compound for further optimization and development for osteoarthritis.",

keywords = "Collagenolysis inhibition, In vitro and in vivo pharmacokinetics, Matrix metalloproteinase 13, Oxetane containing inhibitors, Structure–activity relationship",

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

note = "Funding Information: This research was supported by NIH R01 AR063795 (GBF and WRR). RF was supported by a Schroedinger Postdoctoral Fellowship, financed by the Austrian Science Fund (FWF). Publisher Copyright: {\textcopyright} 2022 Elsevier Ltd",

year = "2022",

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doi = "10.1016/j.bmcl.2022.129014",

language = "English",

volume = "76",

journal = "Bioorganic and Medicinal Chemistry Letters",

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T1 - Development of a putative Zn2+-chelating but highly selective MMP-13 inhibitor

AU - Fürst, Rita

AU - Choi, Jun Yong

AU - Knapinska, Anna M.

AU - Cameron, Michael D.

AU - Ruiz, Claudia

AU - Delmas, Amber

AU - Sundrud, Mark S.

AU - Fields, Gregg B.

AU - Roush, William R.

N1 - Funding Information: This research was supported by NIH R01 AR063795 (GBF and WRR). RF was supported by a Schroedinger Postdoctoral Fellowship, financed by the Austrian Science Fund (FWF). Publisher Copyright: © 2022 Elsevier Ltd

PY - 2022/11/15

Y1 - 2022/11/15

N2 - Starting from an already known MMP-13 inhibitor, 1, we pursued an SAR-approach focusing on optimizing interactions close to the Zn2+ binding site of the enzyme. We found the oxetane containing compound 32 (MMP-13 IC50 = 42 nM), which exhibited complete inhibition of collagenolysis in in vitro studies and an excellent selectivity profile among the MMP family. Interestingly, docking studies propose that the oxetane ring in 32 is oriented towards the Zn2+ ion for chelating the metal ion. Chelating properties of MMP13-inhibitors are often connected with non-selectivity within the enzyme family. Compound 32 demonstrates a rare example where the selectivity can be explained via combinatorial effects of interactions within the S1′ loop and a chelating effect of the oxetane moiety. Furthermore, in vivo pharmacokinetic studies were performed demonstrating a concentration of 1.97 μM of 32 within the synovial fluid of the rat knee joint, which makes the compound a promising lead compound for further optimization and development for osteoarthritis.

AB - Starting from an already known MMP-13 inhibitor, 1, we pursued an SAR-approach focusing on optimizing interactions close to the Zn2+ binding site of the enzyme. We found the oxetane containing compound 32 (MMP-13 IC50 = 42 nM), which exhibited complete inhibition of collagenolysis in in vitro studies and an excellent selectivity profile among the MMP family. Interestingly, docking studies propose that the oxetane ring in 32 is oriented towards the Zn2+ ion for chelating the metal ion. Chelating properties of MMP13-inhibitors are often connected with non-selectivity within the enzyme family. Compound 32 demonstrates a rare example where the selectivity can be explained via combinatorial effects of interactions within the S1′ loop and a chelating effect of the oxetane moiety. Furthermore, in vivo pharmacokinetic studies were performed demonstrating a concentration of 1.97 μM of 32 within the synovial fluid of the rat knee joint, which makes the compound a promising lead compound for further optimization and development for osteoarthritis.

KW - Collagenolysis inhibition

KW - In vitro and in vivo pharmacokinetics

KW - Matrix metalloproteinase 13

KW - Oxetane containing inhibitors

KW - Structure–activity relationship

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DO - 10.1016/j.bmcl.2022.129014

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ER -

Development of a putative Zn2+-chelating but highly selective MMP-13 inhibitor

Abstract

Keywords

ASJC Scopus subject areas

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