title: Discovery of a potent, selective, and orally bioavailable pyridinyl-pyrimidine phthalazine aurora kinase inhibitor.
abstract: The discovery of aurora kinases as essential regulators of cell division has led to intense interest in identifying small molecule aurora kinase inhibitors for the potential treatment of cancer. A high-throughput screening effort identified pyridinyl-pyrimidine 6a as a moderately potent dual inhibitor of aurora kinases -A and -B. Optimization of this hit resulted in an anthranilamide lead (6j) that possessed improved enzyme and cellular activity and exhibited a high level of kinase selectivity. However, this anthranilamide and subsequent analogues suffered from a lack of oral bioavailability. Converting the internally hydrogen-bonded six-membered pseudo-ring of the anthranilamide to a phthalazine (8a-b) led to a dramatic improvement in oral bioavailability (38-61%F) while maintaining the potency and selectivity characteristics of the anthranilamide series. In a COLO 205 tumor pharmacodynamic assay measuring phosphorylation of the aurora-B substrate histone H3 at serine 10 (p-histone H3), oral administration of 8b at 50 mg/kg demonstrated significant reduction in tumor p-histone H3 for at least 6 h.
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142 and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. vcee@amgen.com
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Cee
authors.forename: Laurie B
authors.initials: LB
authors.lastname: Schenkel
authors.forename: Brian L
authors.initials: BL
authors.lastname: Hodous
authors.forename: Holly L
authors.initials: HL
authors.lastname: Deak
authors.forename: Hanh N
authors.initials: HN
authors.lastname: Nguyen
authors.forename: Philip R
authors.initials: PR
authors.lastname: Olivieri
authors.forename: Karina
authors.initials: K
authors.lastname: Romero
authors.forename: Annette
authors.initials: A
authors.lastname: Bak
authors.forename: Xuhai
authors.initials: X
authors.lastname: Be
authors.forename: Steve
authors.initials: S
authors.lastname: Bellon
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Bush
authors.forename: Alan C
authors.initials: AC
authors.lastname: Cheng
authors.forename: Grace
authors.initials: G
authors.lastname: Chung
authors.forename: Steve
authors.initials: S
authors.lastname: Coats
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Eden
authors.forename: Kelly
authors.initials: K
authors.lastname: Hanestad
authors.forename: Paul L
authors.initials: PL
authors.lastname: Gallant
authors.forename: Yan
authors.initials: Y
authors.lastname: Gu
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Richard L
authors.initials: RL
authors.lastname: Kendall
authors.forename: Min-Hwa Jasmine
authors.initials: MH
authors.lastname: Lin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Morrison
authors.forename: Vinod F
authors.initials: VF
authors.lastname: Patel
authors.forename: Robert
authors.initials: R
authors.lastname: Radinsky
authors.forename: Paul E
authors.initials: PE
authors.lastname: Rose
authors.forename: Sandra
authors.initials: S
authors.lastname: Ross
authors.forename: Ji-Rong
authors.initials: JR
authors.lastname: Sun
authors.forename: Jin
authors.initials: J
authors.lastname: Tang
authors.forename: Huilin
authors.initials: H
authors.lastname: Zhao
authors.forename: Marc
authors.initials: M
authors.lastname: Payton
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Geuns-Meyer
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D010793:Phthalazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: C552336:4-(4-fluorophenyl)-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine; D000970:Antineoplastic Agents; D001798:Blood Proteins; D006657:Histones; D010793:Phthalazines; D011725:Pyridines; D011743:Pyrimidines; C576921:AURKB protein, human; C576924:Aurkb protein, mouse; C576925:Aurkb protein, rat; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases