beta-N-Biaryl ether sulfonamide hydroxamates as potent gelatinase inhibitors: part 2. Optimization of alpha-amino substituents.
The introduction and the optimization of an alpha-amino substituent based on a series of alpha-hydroxy-beta-N-biaryl ether sulfonamide hydroxamates is described. The modification leads to a new series of MMP-2/MMP-9 inhibitors with enhanced inhibitory activities and improved ADME properties. An efficacy study on reducing the ischemia-induced brain edema in the rat transient middle cerebral artery occlusion (tMCAo) model is also demonstrated.
Yang
Shyh-Ming
SM
Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 8 Clarke Drive, Cranbury, NJ 08512, USA. syang9@prdus.jnj.com
Scannevin
Robert H
RH
Wang
Bingbing
B
Burke
Sharon L
SL
Huang
Zhihong
Z
Karnachi
Prabha
P
Wilson
Lawrence J
LJ
Rhodes
Kenneth J
KJ
Lagu
Bharat
B
Murray
William V
WV
D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D001929:Brain Edema / Q000139:chemically induced; D004195:Disease Models, Animal; D015195:Drug Design; D018093:Gelatinases / Q000037:antagonists & inhibitors*; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D061965:Matrix Metalloproteinase Inhibitors; D008862:Microsomes, Liver / Q000187:drug effects; D020768:Middle Cerebral Artery / Q000187:drug effects; D015394:Molecular Structure; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000596:Amino Acids; C097658:CGS 27023A; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011719:Pyrazines; D013449:Sulfonamides; D018093:Gelatinases