title: Discovery of pyrazolo[1,5-a]pyrimidine-based CHK1 inhibitors: a template-based approach--part 2.
abstract: Previous efforts by our group have established pyrazolo[1,5-a]pyrimidine as a viable core for the development of potent and selective CDK inhibitors. As part of an effort to utilize the pyrazolo[1,5-a]pyrimidine core as a template for the design and synthesis of potent and selective kinase inhibitors, we focused on a key regulator in the cell cycle progression, CHK1. Continued SAR development of the pyrazolo[1,5-a]pyrimidine core at the C5 and C6 positions, in conjunction with previously disclosed SAR at the C3 and C7 positions, led to the discovery of potent and selective CHK1 inhibitors.
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States. marc.labroli@merck.com
authors.forename: Marc
authors.initials: M
authors.lastname: Labroli
authors.forename: Kamil
authors.initials: K
authors.lastname: Paruch
authors.forename: Michael P
authors.initials: MP
authors.lastname: Dwyer
authors.forename: Carmen
authors.initials: C
authors.lastname: Alvarez
authors.forename: Kartik
authors.initials: K
authors.lastname: Keertikar
authors.forename: Cory
authors.initials: C
authors.lastname: Poker
authors.forename: Randall
authors.initials: R
authors.lastname: Rossman
authors.forename: Jose S
authors.initials: JS
authors.lastname: Duca
authors.forename: Thierry O
authors.initials: TO
authors.lastname: Fischmann
authors.forename: Vincent
authors.initials: V
authors.lastname: Madison
authors.forename: David
authors.initials: D
authors.lastname: Parry
authors.forename: Nicole
authors.initials: N
authors.lastname: Davis
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Seghezzi
authors.forename: Derek
authors.initials: D
authors.lastname: Wiswell
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Guzi
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D000071877:Checkpoint Kinase 1; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C527752:pyrazolo(1,5-a)pyrimidine; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; D051357:Cyclin-Dependent Kinase 2