Synthesis and Evaluation of Indenopyrazoles as Cyclin-Dependent Kinase Inhibitors. 3. Structure Activity Relationships at C3

• Published in: Journal of medicinal chemistry Vol. 45; no. 24; pp. 5233 - 5248
• Main Authors: Yue, Eddy W, Higley, C. Anne, DiMeo, Susan V, Carini, David J, Nugiel, David A, Benware, Carrie, Benfield, Pamela A, Burton, Catherine R, Cox, Sarah, Grafstrom, Robert H, Sharp, Diane M, Sisk, Lisa M, Boylan, John F, Muckelbauer, Jodi K, Smallwood, Angela M, Chen, Haiying, Chang, Chong-Hwan, Seitz, Steven P, Trainor, George L
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 21-11-2002
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Biological and medical sciences; CDC2-CDC28 Kinases; Cell Division - drug effects; Crystallography, X-Ray; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinases - antagonists & inhibitors; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; General aspects; Humans; Kinetics; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Proto-Oncogene Proteins; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Structure-Activity Relationship; Tumor Cells, Cultured; Antineoplastic agent; Nitrogen heterocycle; Furan derivatives; Cytotoxicity; Binding site; Morpholine derivatives; Modeling; Pyrrole derivatives; Thiophene derivatives; Structure activity relation; Molecular model; Piperidine derivatives; Ureas; Aromatic compound; Colon; Chemical synthesis; Human; Enzyme; Transferases; Benzene derivatives; Enzyme inhibitor; Inhibitor enzyme complex; Tricyclic compound; X ray diffraction; In vitro; Cell line; Cell death; Protein kinase; Carboxamide; Fibroblast; Apoptosis; Crystalline structure
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0201722

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.