2-(2-Aminothiazol-4-yl)pyrrolidine-based tartrate diamides as potent, selective and orally bioavailable TACE inhibitors

Chaoyang Dai; Dansu Li; Janeta Popovici-Muller; Lianyun Zhao; Vinay M Girijavallabhan; Kristin E Rosner; Brian J Lavey; Razia Rizvi; Bandarpalle B Shankar; Michael K C Wong; Zhuyan Guo; Peter Orth; Corey O Strickland; Jing Sun; Xiaoda Niu; Shiying Chen; Joseph A Kozlowski; Daniel J Lundell; John J Piwinski; Neng-Yang Shih; M Arshad Siddiqui

doi:10.1016/j.bmcl.2011.01.002

2-(2-Aminothiazol-4-yl)pyrrolidine-based tartrate diamides as potent, selective and orally bioavailable TACE inhibitors

Bioorg Med Chem Lett. 2011 May 15;21(10):3172-6. doi: 10.1016/j.bmcl.2011.01.002. Epub 2011 Jan 6.

Affiliation

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

PMID: 21458257
DOI: 10.1016/j.bmcl.2011.01.002

Abstract

TNF-α converting enzyme (TACE) inhibitors are promising agents to treat inflammatory disorders and cancer. We have investigated novel tartrate diamide TACE inhibitors where the tartrate core binds to zinc in a unique tridentate fashion. Incorporating (R)-2-(2-N-alkylaminothiazol-4-yl)pyrrolidines into the left hand side amide of the tartrate scaffold led to the discovery of potent and selective TACE inhibitors, some of which exhibited good rat oral bioavailability.

MeSH terms

ADAM Proteins / antagonists & inhibitors*
ADAM17 Protein
Amides / chemical synthesis
Amides / chemistry
Amides / pharmacology*
Animals
Biological Availability
Enzyme Activation / drug effects
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Molecular Structure
Pyrrolidines / chemistry*
Rats
Tartrates / chemistry*

Substances

Amides
Enzyme Inhibitors
Pyrrolidines
Tartrates
ADAM Proteins
ADAM17 Protein
Adam17 protein, rat
tartaric acid