title: Structure-based design of 2,6,7-trisubstituted-7H-pyrrolo[2,3-d]pyrimidines as Aurora kinases inhibitors.
abstract: This Letter reports the optimization of a pyrrolopyrimidine series as dual inhibitors of Aurora A/B kinases. This series derived from a pyrazolopyrimidine series previously reported as inhibitors of aurora kinases and CDKs. In an effort to improve the selectivity of this chemotype, we switched to the pyrrolopyrimidine core which allowed functionalization on C-2. In addition, the modeling rationale was based on superimposing the structures of Aurora-A kinase and CDK2 which revealed enough differences leading to a path for selectivity improvement. The synthesis of the new series of pyrrolopyrimidine analogs relied on the development of a different route for the two key intermediates 7 and 19 which led to analogs with both tunable activity against CDK1 and maintained cell potency.
authors.affiliation: Biogen Idec, 5200 Research Place, San Diego, CA 92122, USA. jean@chempartner.com
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Le Brazidec
authors.forename: Angela
authors.initials: A
authors.lastname: Pasis
authors.forename: Betty
authors.initials: B
authors.lastname: Tam
authors.forename: Christina
authors.initials: C
authors.lastname: Boykin
authors.forename: Deping
authors.initials: D
authors.lastname: Wang
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Marcotte
authors.forename: Gisela
authors.initials: G
authors.lastname: Claassen
authors.forename: Jer-Hong
authors.initials: JH
authors.lastname: Chong
authors.forename: Jianhua
authors.initials: J
authors.lastname: Chao
authors.forename: Junhua
authors.initials: J
authors.lastname: Fan
authors.forename: Khanh
authors.initials: K
authors.lastname: Nguyen
authors.forename: Laura
authors.initials: L
authors.lastname: Silvian
authors.forename: Leona
authors.initials: L
authors.lastname: Ling
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: Choi
authors.forename: Min
authors.initials: M
authors.lastname: Teng
authors.forename: Nuzhat
authors.initials: N
authors.lastname: Pathan
authors.forename: Shuo
authors.initials: S
authors.lastname: Zhao
authors.forename: Tony
authors.initials: T
authors.lastname: Li
authors.forename: Art
authors.initials: A
authors.lastname: Taveras
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D064127:Aurora Kinases; D001665:Binding Sites; D016203:CDC2 Protein Kinase / Q000737:chemistry*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002460:Cell Line; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D051357:Cyclin-Dependent Kinase 2