Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis

Mark E. Schnute; Patrick M. O'Brien; Joe Nahra; Mark Morris; W. Howard Roark; Cathleen E. Hanau; Peter G. Ruminski; Jeffrey A. Scholten; Theresa R. Fletcher; Bruce C. Hamper; Jeffery N. Carroll; William C. Patt; Huey S. Shieh; Brandon Collins; Alexander G. Pavlovsky; Katherine E. Palmquist; Karl W. Aston; Jeffrey Hitchcock; Michael D. Rogers; Joseph McDonald; Adam R. Johnson; Grace E. Munie; Arthur J. Wittwer; Chiu Fai Man; Steven L. Settle; Olga Nemirovskiy; Lillian E. Vickery; Arun Agawal; Richard D. Dyer; Teresa Sunyer

doi:10.1016/j.bmcl.2009.11.081

Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis

Mark E. Schnute
, Patrick M. O'Brien
, Joe Nahra
, Mark Morris
, W. Howard Roark
, Cathleen E. Hanau
, Peter G. Ruminski
, Jeffrey A. Scholten
, Theresa R. Fletcher
, Bruce C. Hamper
, Jeffery N. Carroll
, William C. Patt
, Huey S. Shieh
, Brandon Collins
, Alexander G. Pavlovsky
, Katherine E. Palmquist
, Karl W. Aston
, Jeffrey Hitchcock
, Michael D. Rogers
, Joseph McDonald

Adam R. Johnson, Grace E. Munie, Arthur J. Wittwer, Chiu Fai Man, Steven L. Settle, Olga Nemirovskiy, Lillian E. Vickery, Arun Agawal, Richard D. Dyer, Teresa Sunyer

Section of Stem Cell Biology

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

49 Scopus citations

Abstract

Potent, highly selective and orally-bioavailable MMP-13 inhibitors have been identified based upon a (pyridin-4-yl)-2H-tetrazole scaffold. Co-crystal structure analysis revealed that the inhibitors bind at the S₁^′ active site pocket and are not ligands for the catalytic zinc atom. Compound 29b demonstrated reduction of cartilage degradation biomarker (TIINE) levels associated with cartilage protection in a preclinical rat osteoarthritis model.

Original language	English
Pages (from-to)	576-580
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	20
Issue number	2
DOIs	https://doi.org/10.1016/j.bmcl.2009.11.081
State	Published - Jan 15 2010

Keywords

DMOAD
MMP
Osteoarthritis

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10.1016/j.bmcl.2009.11.081

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Schnute, M. E., O'Brien, P. M., Nahra, J., Morris, M., Howard Roark, W., Hanau, C. E., Ruminski, P. G., Scholten, J. A., Fletcher, T. R., Hamper, B. C., Carroll, J. N., Patt, W. C., Shieh, H. S., Collins, B., Pavlovsky, A. G., Palmquist, K. E., Aston, K. W., Hitchcock, J., Rogers, M. D., ... Sunyer, T. (2010). Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis. Bioorganic and Medicinal Chemistry Letters, 20(2), 576-580. https://doi.org/10.1016/j.bmcl.2009.11.081

@article{7556c02ab595425c91cc1c54d9df3a9d,

title = "Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis",

abstract = "Potent, highly selective and orally-bioavailable MMP-13 inhibitors have been identified based upon a (pyridin-4-yl)-2H-tetrazole scaffold. Co-crystal structure analysis revealed that the inhibitors bind at the S1′ active site pocket and are not ligands for the catalytic zinc atom. Compound 29b demonstrated reduction of cartilage degradation biomarker (TIINE) levels associated with cartilage protection in a preclinical rat osteoarthritis model.",

keywords = "DMOAD, MMP, Osteoarthritis",

author = "Schnute, \{Mark E.\} and O'Brien, \{Patrick M.\} and Joe Nahra and Mark Morris and \{Howard Roark\}, W. and Hanau, \{Cathleen E.\} and Ruminski, \{Peter G.\} and Scholten, \{Jeffrey A.\} and Fletcher, \{Theresa R.\} and Hamper, \{Bruce C.\} and Carroll, \{Jeffery N.\} and Patt, \{William C.\} and Shieh, \{Huey S.\} and Brandon Collins and Pavlovsky, \{Alexander G.\} and Palmquist, \{Katherine E.\} and Aston, \{Karl W.\} and Jeffrey Hitchcock and Rogers, \{Michael D.\} and Joseph McDonald and Johnson, \{Adam R.\} and Munie, \{Grace E.\} and Wittwer, \{Arthur J.\} and Man, \{Chiu Fai\} and Settle, \{Steven L.\} and Olga Nemirovskiy and Vickery, \{Lillian E.\} and Arun Agawal and Dyer, \{Richard D.\} and Teresa Sunyer",

year = "2010",

month = jan,

day = "15",

doi = "10.1016/j.bmcl.2009.11.081",

language = "English",

volume = "20",

pages = "576--580",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

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Schnute, ME, O'Brien, PM, Nahra, J, Morris, M, Howard Roark, W, Hanau, CE, Ruminski, PG, Scholten, JA, Fletcher, TR, Hamper, BC, Carroll, JN, Patt, WC, Shieh, HS, Collins, B, Pavlovsky, AG, Palmquist, KE, Aston, KW, Hitchcock, J, Rogers, MD, McDonald, J, Johnson, AR, Munie, GE, Wittwer, AJ, Man, CF, Settle, SL, Nemirovskiy, O, Vickery, LE, Agawal, A, Dyer, RD & Sunyer, T 2010, 'Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis', Bioorganic and Medicinal Chemistry Letters, vol. 20, no. 2, pp. 576-580. https://doi.org/10.1016/j.bmcl.2009.11.081

Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis. / Schnute, Mark E.; O'Brien, Patrick M.; Nahra, Joe et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 20, No. 2, 15.01.2010, p. 576-580.

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

TY - JOUR

T1 - Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis

AU - Schnute, Mark E.

AU - O'Brien, Patrick M.

AU - Nahra, Joe

AU - Morris, Mark

AU - Howard Roark, W.

AU - Hanau, Cathleen E.

AU - Ruminski, Peter G.

AU - Scholten, Jeffrey A.

AU - Fletcher, Theresa R.

AU - Hamper, Bruce C.

AU - Carroll, Jeffery N.

AU - Patt, William C.

AU - Shieh, Huey S.

AU - Collins, Brandon

AU - Pavlovsky, Alexander G.

AU - Palmquist, Katherine E.

AU - Aston, Karl W.

AU - Hitchcock, Jeffrey

AU - Rogers, Michael D.

AU - McDonald, Joseph

AU - Johnson, Adam R.

AU - Munie, Grace E.

AU - Wittwer, Arthur J.

AU - Man, Chiu Fai

AU - Settle, Steven L.

AU - Nemirovskiy, Olga

AU - Vickery, Lillian E.

AU - Agawal, Arun

AU - Dyer, Richard D.

AU - Sunyer, Teresa

PY - 2010/1/15

Y1 - 2010/1/15

N2 - Potent, highly selective and orally-bioavailable MMP-13 inhibitors have been identified based upon a (pyridin-4-yl)-2H-tetrazole scaffold. Co-crystal structure analysis revealed that the inhibitors bind at the S1′ active site pocket and are not ligands for the catalytic zinc atom. Compound 29b demonstrated reduction of cartilage degradation biomarker (TIINE) levels associated with cartilage protection in a preclinical rat osteoarthritis model.

AB - Potent, highly selective and orally-bioavailable MMP-13 inhibitors have been identified based upon a (pyridin-4-yl)-2H-tetrazole scaffold. Co-crystal structure analysis revealed that the inhibitors bind at the S1′ active site pocket and are not ligands for the catalytic zinc atom. Compound 29b demonstrated reduction of cartilage degradation biomarker (TIINE) levels associated with cartilage protection in a preclinical rat osteoarthritis model.

KW - DMOAD

KW - MMP

KW - Osteoarthritis

UR - https://www.scopus.com/pages/publications/72249087935

U2 - 10.1016/j.bmcl.2009.11.081

DO - 10.1016/j.bmcl.2009.11.081

M3 - Article

C2 - 20005097

AN - SCOPUS:72249087935

SN - 0960-894X

VL - 20

SP - 576

EP - 580

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 2

ER -

Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis

Abstract

Keywords

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