title: Synthesis, SAR study and biological evaluation of novel pyrazolo[1,5-a]pyrimidin-7-yl phenyl amides as anti-proliferative agents.
abstract: Checkpoint deficiency of malignant cells can be exploited in cancer drug discovery. Compounds that selectively kill checkpoint-deficient cells versus checkpoint-proficient cells can be utilized to preferentially target tumor cells, while sparing normal cells. The protein p21(Wafl/Cipl/Sdi1) (hereafter referred to as p21) inhibits progression of the cell cycle by inhibiting the activity of G1 kinases (cyclin D/cdk4 and cyclin E-cdk2) and the G2 kinase (cyclin B/cdkl) in response to DNA damage or abnormal DNA content. The expression of p21 is often low in human cancer cells due to frequent loss of the upstream activator, p53, and is associated with poor prognosis in some cancer patients. Using an isogenic pair of cell lines, HCT116 (p21+/+) and 80S14 (p21-/-), we have disclosed previously a novel series of pyrazolo[1,5-a]pyrimidines that preferentially kill the p21-deficient cells. We will present the synthesis, biological activities and SAR study of a series of pyrazolo[1,5-a]pyrimidines with an optimized phenyl amide moiety at the C-7 position. The mechanism of action of these compounds will also be discussed.
authors.affiliation: Chemical and Screening Sciences, Wyeth Research, Pearl River, NY 10965, USA. wangd@wyeth.com
authors.forename: Yanong D
authors.initials: YD
authors.lastname: Wang
authors.forename: Erick
authors.initials: E
authors.lastname: Honores
authors.forename: Biqi
authors.initials: B
authors.lastname: Wu
authors.forename: Steve
authors.initials: S
authors.lastname: Johnson
authors.forename: Dennis
authors.initials: D
authors.lastname: Powell
authors.forename: Miriam
authors.initials: M
authors.lastname: Miranda
authors.forename: John P
authors.initials: JP
authors.lastname: McGinnis
authors.forename: Carolyn
authors.initials: C
authors.lastname: Discafani
authors.forename: Sridhar K
authors.initials: SK
authors.lastname: Rabindran
authors.forename: Wendy
authors.initials: W
authors.lastname: Cheng
authors.forename: Girija
authors.initials: G
authors.lastname: Krishnamurthy
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011720:Pyrazoles / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D011720:Pyrazoles; D011743:Pyrimidines; C527752:pyrazolo(1,5-a)pyrimidine; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4