Synthesis and SAR of diazepine and thiazepine TACE and MMP inhibitors

Arie Zask; Joshua Kaplan; XueMei Du; Gloria MacEwan; Vincent Sandanayaka; Nancy Eudy; Jeremy Levin; Guixian Jin; Jun Xu; Terri Cummons; Dauphine Barone; Semiramis Ayral-Kaloustian; Jerauld Skotnicki

doi:10.1016/j.bmcl.2005.01.053

Synthesis and SAR of diazepine and thiazepine TACE and MMP inhibitors

Bioorg Med Chem Lett. 2005 Mar 15;15(6):1641-5. doi: 10.1016/j.bmcl.2005.01.053.

Authors

Arie Zask¹, Joshua Kaplan, XueMei Du, Gloria MacEwan, Vincent Sandanayaka, Nancy Eudy, Jeremy Levin, Guixian Jin, Jun Xu, Terri Cummons, Dauphine Barone, Semiramis Ayral-Kaloustian, Jerauld Skotnicki

Affiliation

¹ Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. zaska@wyeth.com

PMID: 15745814
DOI: 10.1016/j.bmcl.2005.01.053

Abstract

Potent and selective TACE and MMP inhibitors utilizing the diazepine and thiazepine ring systems were synthesized and evaluated for biological activity in in vitro and in vivo models of TNF-alpha release. Oral activity in the mouse LPS model of TNF-alpha release was seen. Efficacy in the mouse collagen induced arthritis model was achieved with diazepine 20.

MeSH terms

ADAM Proteins
ADAM17 Protein
Animals
Azepines / chemical synthesis
Azepines / chemistry*
Azepines / pharmacology*
Female
Matrix Metalloproteinase Inhibitors*
Metalloendopeptidases / antagonists & inhibitors*
Mice
Mice, Inbred BALB C
Models, Chemical
Molecular Structure
Structure-Activity Relationship

Substances

Azepines
Matrix Metalloproteinase Inhibitors
ADAM Proteins
Metalloendopeptidases
ADAM17 Protein
Adam17 protein, mouse