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).
Watterson SH,
Chen P,
Zhao Y,
Gu HH,
Dhar TG,
Xiao Z,
Ballentine SK,
Shen Z,
Fleener CA,
Rouleau KA,
Obermeier M,
Yang Z,
McIntyre KW,
Shuster DJ,
Witmer M,
Dambach D,
Chao S,
Mathur A,
Chen BC,
Barrish JC,
Robl JA,
Townsend R,
Iwanowicz EJ.
Bristol-Myers Squibb Pharmaceutical Research Institute, Post Office Box 4000, Princeton, New Jersey 08543, USA. scott.watterson@bms.com
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.
PMID: 17585753 [PubMed - indexed for MEDLINE]