3,4-Disubstituted benzofuran P1' MMP-13 inhibitors: optimization of selectivity and reduction of protein binding

Wei Li; Yonghan Hu; Jianchang Li; Jennifer R Thomason; Dianne DeVincentis; Xuemei Du; Junjun Wu; Rajeev Hotchandani; Thomas S Rush 3rd; Jerauld S Skotnicki; Steve Tam; Priya S Chockalingam; Elisabeth A Morris; Jeremy I Levin

doi:10.1016/j.bmcl.2009.07.008

3,4-Disubstituted benzofuran P1' MMP-13 inhibitors: optimization of selectivity and reduction of protein binding

Bioorg Med Chem Lett. 2009 Aug 15;19(16):4546-50. doi: 10.1016/j.bmcl.2009.07.008. Epub 2009 Jul 9.

Authors

Wei Li¹, Yonghan Hu, Jianchang Li, Jennifer R Thomason, Dianne DeVincentis, Xuemei Du, Junjun Wu, Rajeev Hotchandani, Thomas S Rush 3rd, Jerauld S Skotnicki, Steve Tam, Priya S Chockalingam, Elisabeth A Morris, Jeremy I Levin

Affiliation

¹ Department of Chemical Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, MA 02140, USA.

PMID: 19625186
DOI: 10.1016/j.bmcl.2009.07.008

Abstract

Potent 3,4-disubstituted benzofuran P1' MMP-13 inhibitors have been prepared. Selectivity over MMP-2 was achieved through a substituent at the C4 position of the benzofuran P1' moiety of the molecule. By replacing a backbone benzene with a pyridine and valine with threonine, compounds (e.g., 44) with greatly reduced plasma protein binding were also obtained.

MeSH terms

Animals
Benzofurans / chemical synthesis
Benzofurans / chemistry*
Benzofurans / pharmacology
Matrix Metalloproteinase 13 / metabolism
Matrix Metalloproteinase 2 / metabolism
Matrix Metalloproteinase Inhibitors*
Protease Inhibitors / chemical synthesis
Protease Inhibitors / chemistry*
Protease Inhibitors / pharmacology
Protein Binding
Rabbits
Serum Albumin / chemistry
Structure-Activity Relationship

Substances

Benzofurans
Matrix Metalloproteinase Inhibitors
Protease Inhibitors
Serum Albumin
Matrix Metalloproteinase 13
Matrix Metalloproteinase 2