N-hydroxyformamide peptidomimetics as TACE/matrix metalloprotease inhibitors: oral activity via P1' isobutyl substitution

D L Musso; M W Andersen; R C Andrews; R Austin; E J Beaudet; J D Becherer; D G Bubacz; D M Bickett; J H Chan; J G Conway; D J Cowan; M D Gaul; K C Glennon; K M Hedeen; M H Lambert; M A Leesnitzer; D L McDougald; J L Mitchell; M L Moss; M H Rabinowitz; M C Rizzolio; L T Schaller; J B Stanford; T Tippin; J R Warner; L G Whitesell; R W Wiethe

doi:10.1016/s0960-894x(01)00377-8

N-hydroxyformamide peptidomimetics as TACE/matrix metalloprotease inhibitors: oral activity via P1' isobutyl substitution

Bioorg Med Chem Lett. 2001 Aug 20;11(16):2147-51. doi: 10.1016/s0960-894x(01)00377-8.

Affiliation

¹ GlaxoSmithKline Research and Development, Five Moore Drive, Research Triangle Park, NC 27709, USA. dm12907@glaxowellcome.com

PMID: 11514157
DOI: 10.1016/s0960-894x(01)00377-8

Abstract

N-Hydroxyformamide-class metalloprotease inhibitors were designed and synthesized, which have potent broad-spectrum activity versus matrix metalloproteases and TNF-alpha converting enzyme (TACE). Compound 13c possesses good oral and intravenous pharmacokinetics in the rat and dog.

MeSH terms

ADAM Proteins
ADAM17 Protein
Animals
Dogs
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacokinetics
Enzyme Inhibitors / pharmacology*
Formamides / chemistry
Formamides / pharmacology*
Matrix Metalloproteinase Inhibitors*
Metalloendopeptidases / antagonists & inhibitors*
Oligopeptides / chemistry
Oligopeptides / pharmacology*
Rats
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Formamides
Matrix Metalloproteinase Inhibitors
Oligopeptides
ADAM Proteins
Metalloendopeptidases
ADAM17 Protein
Adam17 protein, rat