Acridone-based inhibitors of inosine 5'-monophosphate dehydrogenase: discovery and SAR leading to the identification of N-(2-(6-(4-ethylpiperazin-1-yl)pyridin-3-yl)propan-2-yl)-2- fluoro-9-oxo-9,10-dihydroacridine-3-carboxamide (BMS-566419).
Inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo synthesis of guanosine nucleotides, catalyzes the irreversible nicotinamide-adenine dinucleotide dependent oxidation of inosine-5'-monophosphate to xanthosine-5'-monophosphate. Mycophenolate Mofetil (MMF), a prodrug of mycophenolic acid, has clinical utility for the treatment of transplant rejection based on its inhibition of IMPDH. The overall clinical benefit of MMF is limited by what is generally believed to be compound-based, dose-limiting gastrointestinal (GI) toxicity that is related to its specific pharmacokinetic characteristics. Thus, development of an IMPDH inhibitor with a novel structure and a different pharmacokinetic profile may reduce the likelihood of GI toxicity and allow for increased efficacy. This article will detail the discovery and SAR leading to a novel and potent acridone-based IMPDH inhibitor 4m and its efficacy and GI tolerability when administered orally in a rat adjuvant arthritis model.
Watterson
Scott H
SH
Bristol-Myers Squibb Pharmaceutical Research Institute, Post Office Box 4000, Princeton, New Jersey 08543, USA. scott.watterson@bms.com
Chen
Ping
P
Zhao
Yufen
Y
Gu
Henry H
HH
Dhar
T G Murali
TG
Xiao
Zili
Z
Ballentine
Shelley K
SK
Shen
Zhongqi
Z
Fleener
Catherine A
CA
Rouleau
Katherine A
KA
Obermeier
Mary
M
Yang
Zheng
Z
McIntyre
Kim W
KW
Shuster
David J
DJ
Witmer
Mark
M
Dambach
Donna
D
Chao
Sam
S
Mathur
Arvind
A
Chen
Bang-Chi
BC
Barrish
Joel C
JC
Robl
Jeffrey A
JA
Townsend
Robert
R
Iwanowicz
Edwin J
EJ
D000166:Acridines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D000284:Administration, Oral; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D001682:Biological Availability; D002460:Cell Line; D049109:Cell Proliferation; D041981:Gastrointestinal Tract / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D011917:Rats, Inbred Lew; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000166:Acridines; C523435:N-(2-(6-(4-ethylpiperazin-1-yl)pyridin-3-yl)propan-2-yl)-2-fluoro-9-oxo-9,10-dihydroacridine-3-carboxamide; D010879:Piperazines; D007168:IMP Dehydrogenase