Novel thiol-based TACE inhibitors. Part 2: Rational design, synthesis, and SAR of thiol-containing aryl sulfones

Upul K Bandarage; Tiansheng Wang; Jon H Come; Emanuele Perola; Yunyi Wei; B Govinda Rao

doi:10.1016/j.bmcl.2007.11.014

Novel thiol-based TACE inhibitors. Part 2: Rational design, synthesis, and SAR of thiol-containing aryl sulfones

Bioorg Med Chem Lett. 2008 Jan 1;18(1):44-8. doi: 10.1016/j.bmcl.2007.11.014. Epub 2007 Nov 13.

Authors

Upul K Bandarage¹, Tiansheng Wang, Jon H Come, Emanuele Perola, Yunyi Wei, B Govinda Rao

Affiliation

¹ Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, MA 02139, USA. upul_bandarage@vrtx.com

PMID: 18054488
DOI: 10.1016/j.bmcl.2007.11.014

Abstract

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

MeSH terms

ADAM Proteins / antagonists & inhibitors*
ADAM17 Protein
Crystallography, X-Ray
Drug Design
Isoenzymes / antagonists & inhibitors
Kinetics
Metalloendopeptidases / antagonists & inhibitors
Models, Molecular
Protease Inhibitors / chemical synthesis*
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology*
Structure-Activity Relationship
Substrate Specificity
Sulfhydryl Compounds / chemical synthesis*
Sulfhydryl Compounds / chemistry
Sulfhydryl Compounds / pharmacology*
Sulfones / chemical synthesis*
Sulfones / chemistry
Sulfones / pharmacology*

Substances

Isoenzymes
Protease Inhibitors
Sulfhydryl Compounds
Sulfones
ADAM Proteins
Metalloendopeptidases
ADAM17 Protein