title: Design, synthesis and biological evaluation of novel inosine 5'-monophosphate dehydrogenase (IMPDH) inhibitors.
abstract: This study is based on our attempts to further explore the structure-activity relationship (SAR) of VX-148 (3) in an attempt to identify inosine 5'-mono-phosphate dehydrogenase (IMPDH) inhibitors superior to mycophenolic acid. A five-point pharmacophore developed using structurally diverse, known IMPDH inhibitors guided further design of novel analogs of 3. Several conventional as well as novel medicinal chemistry strategies were tried. The combined structure- and ligand-based approaches culminated in a few analogs with either retained or slightly higher potency. The compounds which retained the potency were also checked for their ability to inhibit human peripheral blood mononuclear cells proliferation. This study illuminates the stringent structural requirements and strict SAR for IMPDH II inhibition.
authors.affiliation: Global Discovery, Nycomed: a Takeda Company, Nycomed GmbH , Konstanz , Germany .
authors.forename: Torsten
authors.initials: T
authors.lastname: Dunkern
authors.forename: Sunil
authors.initials: S
authors.lastname: Chavan
authors.forename: Digambar
authors.initials: D
authors.lastname: Bankar
authors.forename: Anuja
authors.initials: A
authors.lastname: Patil
authors.forename: Pritee
authors.initials: P
authors.lastname: Kulkarni
authors.forename: Prashant S
authors.initials: PS
authors.lastname: Kharkar
authors.forename: Arati
authors.initials: A
authors.lastname: Prabhu
authors.forename: Heike
authors.initials: H
authors.lastname: Goebel
authors.forename: Edith
authors.initials: E
authors.lastname: Rolser
authors.forename: Waltraud
authors.initials: W
authors.lastname: Burckhard-Boer
authors.forename: Premkumar
authors.initials: P
authors.lastname: Arumugam
authors.forename: Mahindra T
authors.initials: MT
authors.lastname: Makhija
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D009173:Mycophenolic Acid / Q000737:chemistry / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D010671:Phenylurea Compounds; C465281:VX148; D007168:IMP Dehydrogenase; C488211:IMPDH1 protein, human; C501687:IMPDH2 protein, human; D009173:Mycophenolic Acid
keywords: 3D pharmacophore; IMPDH; VX-148; advanced chemical analog; immunosuppressant