The design and synthesis of novel N-hydroxyformamide inhibitors of ADAM-TS4 for the treatment of osteoarthritis

Chris De Savi; Andrew Pape; John G. Cumming; Attilla Ting; Peter D. Smith; Jeremy N. Burrows; Mark Mills; Chris Davies; Scott Lamont; David Milne; Calum Cook; Peter Moore; Yvonne Sawyer; Stefan Gerhardt

doi:10.1016/j.bmcl.2011.01.036

The design and synthesis of novel N-hydroxyformamide inhibitors of ADAM-TS4 for the treatment of osteoarthritis

Chris De Savi
, Andrew Pape
, John G. Cumming
, Attilla Ting
, Peter D. Smith
, Jeremy N. Burrows
, Mark Mills
, Chris Davies
, Scott Lamont
, David Milne
, Calum Cook
, Peter Moore
, Yvonne Sawyer
, Stefan Gerhardt

AstraZeneca

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

23 Citations (Scopus)

Abstract

Two series of N-hydroxyformamide inhibitors of ADAM-TS4 were identified from screening compounds previously synthesised as inhibitors of matrix metalloproteinase-13 (collagenase-3). Understanding of the binding mode of this class of compound using ADAM-TS1 as a structural surrogate has led to the discovery of potent and very selective inhibitors with favourable DMPK properties. Synthesis, structure-activity relationships, and strategies to improve selectivity and lower in vivo metabolic clearance are described.

Original language	English
Pages (from-to)	1376-1381
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	5
DOIs	https://doi.org/10.1016/j.bmcl.2011.01.036
Publication status	Published - 1 Mar 2011
Externally published	Yes

Keywords

ADAM-TS4
Aggrecanases
Cyp inhibition
MMP-13
Osteoarthritis
Reverse hydroxamates

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10.1016/j.bmcl.2011.01.036

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De Savi, C., Pape, A., Cumming, J. G., Ting, A., Smith, P. D., Burrows, J. N., Mills, M., Davies, C., Lamont, S., Milne, D., Cook, C., Moore, P., Sawyer, Y., & Gerhardt, S. (2011). The design and synthesis of novel N-hydroxyformamide inhibitors of ADAM-TS4 for the treatment of osteoarthritis. Bioorganic and Medicinal Chemistry Letters, 21(5), 1376-1381. https://doi.org/10.1016/j.bmcl.2011.01.036

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title = "The design and synthesis of novel N-hydroxyformamide inhibitors of ADAM-TS4 for the treatment of osteoarthritis",

abstract = "Two series of N-hydroxyformamide inhibitors of ADAM-TS4 were identified from screening compounds previously synthesised as inhibitors of matrix metalloproteinase-13 (collagenase-3). Understanding of the binding mode of this class of compound using ADAM-TS1 as a structural surrogate has led to the discovery of potent and very selective inhibitors with favourable DMPK properties. Synthesis, structure-activity relationships, and strategies to improve selectivity and lower in vivo metabolic clearance are described.",

keywords = "ADAM-TS4, Aggrecanases, Cyp inhibition, MMP-13, Osteoarthritis, Reverse hydroxamates",

author = "\{De Savi\}, Chris and Andrew Pape and Cumming, \{John G.\} and Attilla Ting and Smith, \{Peter D.\} and Burrows, \{Jeremy N.\} and Mark Mills and Chris Davies and Scott Lamont and David Milne and Calum Cook and Peter Moore and Yvonne Sawyer and Stefan Gerhardt",

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doi = "10.1016/j.bmcl.2011.01.036",

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journal = "Bioorganic and Medicinal Chemistry Letters",

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De Savi, C, Pape, A, Cumming, JG, Ting, A, Smith, PD, Burrows, JN, Mills, M, Davies, C, Lamont, S, Milne, D, Cook, C, Moore, P, Sawyer, Y & Gerhardt, S 2011, 'The design and synthesis of novel N-hydroxyformamide inhibitors of ADAM-TS4 for the treatment of osteoarthritis', Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 5, pp. 1376-1381. https://doi.org/10.1016/j.bmcl.2011.01.036

TY - JOUR

T1 - The design and synthesis of novel N-hydroxyformamide inhibitors of ADAM-TS4 for the treatment of osteoarthritis

AU - De Savi, Chris

AU - Pape, Andrew

AU - Cumming, John G.

AU - Ting, Attilla

AU - Smith, Peter D.

AU - Burrows, Jeremy N.

AU - Mills, Mark

AU - Davies, Chris

AU - Lamont, Scott

AU - Milne, David

AU - Cook, Calum

AU - Moore, Peter

AU - Sawyer, Yvonne

AU - Gerhardt, Stefan

PY - 2011/3/1

Y1 - 2011/3/1

N2 - Two series of N-hydroxyformamide inhibitors of ADAM-TS4 were identified from screening compounds previously synthesised as inhibitors of matrix metalloproteinase-13 (collagenase-3). Understanding of the binding mode of this class of compound using ADAM-TS1 as a structural surrogate has led to the discovery of potent and very selective inhibitors with favourable DMPK properties. Synthesis, structure-activity relationships, and strategies to improve selectivity and lower in vivo metabolic clearance are described.

AB - Two series of N-hydroxyformamide inhibitors of ADAM-TS4 were identified from screening compounds previously synthesised as inhibitors of matrix metalloproteinase-13 (collagenase-3). Understanding of the binding mode of this class of compound using ADAM-TS1 as a structural surrogate has led to the discovery of potent and very selective inhibitors with favourable DMPK properties. Synthesis, structure-activity relationships, and strategies to improve selectivity and lower in vivo metabolic clearance are described.

KW - ADAM-TS4

KW - Aggrecanases

KW - Cyp inhibition

KW - MMP-13

KW - Osteoarthritis

KW - Reverse hydroxamates

U2 - 10.1016/j.bmcl.2011.01.036

DO - 10.1016/j.bmcl.2011.01.036

M3 - Article

C2 - 21300546

AN - SCOPUS:79951692827

SN - 0960-894X

VL - 21

SP - 1376

EP - 1381

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 5

ER -

The design and synthesis of novel N-hydroxyformamide inhibitors of ADAM-TS4 for the treatment of osteoarthritis

Abstract

Keywords

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