2. Academic Validation
  3. 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)

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)

  • J Med Chem. 2007 Jul 26;50(15):3730-42. doi: 10.1021/jm070299x.
Scott H Watterson 1,  Ping Chen,  Yufen Zhao,  Henry H Gu,  T G Murali Dhar,  Zili Xiao,  Shelley K Ballentine,  Zhongqi Shen,  Catherine A Fleener,  Katherine A Rouleau,  Mary Obermeier,  Zheng Yang,  Kim W McIntyre,  David J Shuster,  Mark Witmer,  Donna Dambach,  Sam Chao,  Arvind Mathur,  Bang-Chi Chen,  Joel C Barrish,  Jeffrey A Robl,  Robert Townsend,  Edwin J Iwanowicz
Affiliations

Affiliation

  • 1 Bristol-Myers Squibb Pharmaceutical Research Institute, Post Office Box 4000, Princeton, New Jersey 08543, USA. scott.watterson@bms.com
PMID: 17585753 DOI: 10.1021/jm070299x
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-110217
    99.68%, IMPDH Inhibitor