Novel thiol-based TACE inhibitors: rational design, synthesis, and SAR of thiol-containing aryl sulfonamides

B Govinda Rao; Upul K Bandarage; Tiansheng Wang; Jon H Come; Emanuele Perola; Yunyi Wei; Shi-Kai Tian; Jeffrey O Saunders

doi:10.1016/j.bmcl.2007.01.064

Novel thiol-based TACE inhibitors: rational design, synthesis, and SAR of thiol-containing aryl sulfonamides

Bioorg Med Chem Lett. 2007 Apr 15;17(8):2250-3. doi: 10.1016/j.bmcl.2007.01.064. Epub 2007 Jan 26.

Authors

B Govinda Rao¹, Upul K Bandarage, Tiansheng Wang, Jon H Come, Emanuele Perola, Yunyi Wei, Shi-Kai Tian, Jeffrey O Saunders

Affiliation

¹ Vertex Pharmaceuticals Inc., 130 Waverly Street, Cambridge, MA 02139, USA. govinda_rao@vrtx.com

PMID: 17289381
DOI: 10.1016/j.bmcl.2007.01.064

Abstract

A series of potent thiol-containing aryl sulfonamide TACE inhibitors was designed and synthesized. The SAR and MMP selectivity of the series were investigated. In particular, compound 4b has shown excellent in vitro potency against the isolated TACE enzyme and good selectivity over MMP-2, -7, -8, -9, and -13. The X-ray structure of 4b bound to TACE was obtained.

MeSH terms

ADAM Proteins / antagonists & inhibitors*
ADAM17 Protein
Arthritis, Rheumatoid / drug therapy
Crohn Disease / drug therapy
Drug Design*
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology
Humans
Metalloproteases
Structure-Activity Relationship
Substrate Specificity
Sulfhydryl Compounds
Sulfonamides / chemical synthesis*
Sulfonamides / pharmacology

Substances

Enzyme Inhibitors
Sulfhydryl Compounds
Sulfonamides
Metalloproteases
ADAM Proteins
ADAM17 Protein
ADAM17 protein, human