Design and synthesis of 4-quinolinone 2-carboxamides as calpain inhibitors.
Calpains are involved in a variety of calcium-regulated cellular processes, such as signal transduction, cell proliferation, differentiation, and apoptosis. Excessive calpain activation contributes to serious cellular damage and has been reported in many pathological conditions. 4-Quinolinone 2-carboxamide derivatives were prepared and evaluated for mu-calpain inhibitory activities. Of the compounds synthesized, 3a and 3k, which possess a primary amide and 4-methoxyphenethyl amide at P1' region, were found to most potently inhibit mu-calpain with IC50 values of 0.71+/-0.07 and 0.73+/-0.23 microM, respectively. On the other hand, the incorporation of pyridine-containing amides decreased inhibitory activity.
Nam
Dong Hyuk
DH
Department of Pharmaceutical Sciences, Kyung Hee East-West Pharmaceutical Research Institute, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.
Lee
Kwang Seob
KS
Kim
Sang Hoon
SH
Kim
Sung Min
SM
Jung
Seo Yun
SY
Chung
Sung Hyun
SH
Kim
Hyoung Ja
HJ
Kim
Nam Doo
ND
Jin
Changbae
C
Lee
Yong Sup
YS
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002154:Calpain / Q000037:antagonists & inhibitors*; D015195:Drug Design; D006860:Hydrogen Bonding; D007700:Kinetics; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000577:Amides; D011480:Protease Inhibitors; D015363:Quinolones; D002154:Calpain