title: Synthesis and evaluation of indenopyrazoles as cyclin-dependent kinase inhibitors. 3. Structure activity relationships at C3(1,2).
abstract: The identification of indeno[1,2-c]pyrazol-4-ones as inhibitors of cyclin-dependent kinases (CDKs) has led to the discovery of a series of novel and potent compounds. Herein, we report the effects of substitutions at C3 of the indeno[1,2-c]pyrazol-4-one core with alkyls, heterocycles, and substituted phenyls. Substitutions at the para position of the phenyl ring at C3 were generally well-tolerated; however, larger groups were generally inactive. For alkyls directly attached to C3, longer chain substituents were not tolerated; however, shorter alkyl groups and cyclic alkyls were acceptable. In general, the heterocycles at C3 gave the most potent analogues. One such heterocycle, 24j, was examined in detail and was determined to have a biological profile consistent with CDK inhibition. An X-ray crystal structure of one of the alkyl compounds, 13q, complexed with CDK2 was determined and showed the inhibitor residing in the adenosine 5'-triphosphate pocket of the enzyme.
authors.affiliation: Bristol-Myers Squibb Company, Experimental Station, P.O. Box 80500, Wilmington, Delaware 19880-0500, USA. eddy.yue@bms.com
authors.forename: Eddy W
authors.initials: EW
authors.lastname: Yue
authors.forename: C Anne
authors.initials: CA
authors.lastname: Higley
authors.forename: Susan V
authors.initials: SV
authors.lastname: DiMeo
authors.forename: David J
authors.initials: DJ
authors.lastname: Carini
authors.forename: David A
authors.initials: DA
authors.lastname: Nugiel
authors.forename: Carrie
authors.initials: C
authors.lastname: Benware
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Benfield
authors.forename: Catherine R
authors.initials: CR
authors.lastname: Burton
authors.forename: Sarah
authors.initials: S
authors.lastname: Cox
authors.forename: Robert H
authors.initials: RH
authors.lastname: Grafstrom
authors.forename: Diane M
authors.initials: DM
authors.lastname: Sharp
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Sisk
authors.forename: John F
authors.initials: JF
authors.lastname: Boylan
authors.forename: Jodi K
authors.initials: JK
authors.lastname: Muckelbauer
authors.forename: Angela M
authors.initials: AM
authors.lastname: Smallwood
authors.forename: Haiying
authors.initials: H
authors.lastname: Chen
authors.forename: Chong-Hwan
authors.initials: CH
authors.lastname: Chang
authors.forename: Steven P
authors.initials: SP
authors.lastname: Seitz
authors.forename: George L
authors.initials: GL
authors.lastname: Trainor
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D042846:CDC2-CDC28 Kinases; D002455:Cell Division / Q000187:drug effects; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases