title: 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).
abstract: 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.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Post Office Box 4000, Princeton, New Jersey 08543, USA. scott.watterson@bms.com
authors.forename: Scott H
authors.initials: SH
authors.lastname: Watterson
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Yufen
authors.initials: Y
authors.lastname: Zhao
authors.forename: Henry H
authors.initials: HH
authors.lastname: Gu
authors.forename: T G Murali
authors.initials: TG
authors.lastname: Dhar
authors.forename: Zili
authors.initials: Z
authors.lastname: Xiao
authors.forename: Shelley K
authors.initials: SK
authors.lastname: Ballentine
authors.forename: Zhongqi
authors.initials: Z
authors.lastname: Shen
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Fleener
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Rouleau
authors.forename: Mary
authors.initials: M
authors.lastname: Obermeier
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.forename: Kim W
authors.initials: KW
authors.lastname: McIntyre
authors.forename: David J
authors.initials: DJ
authors.lastname: Shuster
authors.forename: Mark
authors.initials: M
authors.lastname: Witmer
authors.forename: Donna
authors.initials: D
authors.lastname: Dambach
authors.forename: Sam
authors.initials: S
authors.lastname: Chao
authors.forename: Arvind
authors.initials: A
authors.lastname: Mathur
authors.forename: Bang-Chi
authors.initials: BC
authors.lastname: Chen
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Robl
authors.forename: Robert
authors.initials: R
authors.lastname: Townsend
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: Iwanowicz
mesh_terms: 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
chemical_list: 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