Structure and activity relationships of tartrate-based TACE inhibitors

Dansu Li; Janeta Popovici-Muller; David B Belanger; John Caldwell; Chaoyang Dai; Maria David; Vinay M Girijavallabhan; Brian J Lavey; Joe F Lee; Zhidan Liu; Rob Mazzola; Razia Rizvi; Kristin E Rosner; Bandarpalle Shankar; Jim Spitler; Pauline C Ting; Henry Vaccaro; Wensheng Yu; Guowei Zhou; Zhaoning Zhu; Xiaoda Niu; Jing Sun; Zhuyan Guo; Peter Orth; Shiying Chen; Joseph A Kozlowski; Daniel J Lundell; Vincent Madison; Brian McKittrick; John J Piwinski; Neng-Yang Shih; Gerald W Shipps Jr; M Arshad Siddiqui; Corey O Strickland

doi:10.1016/j.bmcl.2010.06.104

Structure and activity relationships of tartrate-based TACE inhibitors

Bioorg Med Chem Lett. 2010 Aug 15;20(16):4812-5. doi: 10.1016/j.bmcl.2010.06.104. Epub 2010 Jun 25.

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Cambridge, 320 Bent Street, Cambridge, MA 02141, United States. [email protected]

PMID: 20638281
DOI: 10.1016/j.bmcl.2010.06.104

Abstract

The syntheses and structure-activity relationships of the tartrate-based TACE inhibitors are discussed. The optimization of both the prime and non-prime sites led to compounds with picomolar activity. Several analogs demonstrated good rat pharmacokinetics.

MeSH terms

ADAM Proteins / antagonists & inhibitors*
ADAM Proteins / metabolism
ADAM17 Protein
Animals
Binding Sites
Computer Simulation
Protease Inhibitors / chemical synthesis
Protease Inhibitors / chemistry*
Protease Inhibitors / pharmacokinetics
Rats
Structure-Activity Relationship
Tartrates / chemical synthesis
Tartrates / chemistry*
Tartrates / pharmacokinetics

Substances

Protease Inhibitors
Tartrates
ADAM Proteins
ADAM17 Protein
Adam17 protein, rat