title: A selective, orally bioavailable 1,2,4-triazolo[1,5-a]pyridine-based inhibitor of Janus kinase 2 for use in anticancer therapy: discovery of CEP-33779.
abstract: Members of the JAK family of nonreceptor tyrosine kinases play a critical role in the growth and progression of many cancers and in inflammatory diseases. JAK2 has emerged as a leading therapeutic target for oncology, providing a rationale for the development of a selective JAK2 inhibitor. A program to optimize selective JAK2 inhibitors to combat cancer while reducing the risk of immune suppression associated with JAK3 inhibition was undertaken. The structure-activity relationships and biological evaluation of a novel series of compounds based on a 1,2,4-triazolo[1,5-a]pyridine scaffold are reported. Para substitution on the aryl at the C8 position of the core was optimum for JAK2 potency (17). Substitution at the C2 nitrogen position was required for cell potency (21). Interestingly, meta substitution of C2-NH-aryl moiety provided exceptional selectivity for JAK2 over JAK3 (23). These efforts led to the discovery of CEP-33779 (29), a novel, selective, and orally bioavailable inhibitor of JAK2.
authors.affiliation: Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States. bdugan@cephalon.com
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Dugan
authors.forename: Diane E
authors.initials: DE
authors.lastname: Gingrich
authors.forename: Eugen F
authors.initials: EF
authors.lastname: Mesaros
authors.forename: Karen L
authors.initials: KL
authors.lastname: Milkiewicz
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Curry
authors.forename: Allison L
authors.initials: AL
authors.lastname: Zulli
authors.forename: Pawel
authors.initials: P
authors.lastname: Dobrzanski
authors.forename: Cynthia
authors.initials: C
authors.lastname: Serdikoff
authors.forename: Mahfuza
authors.initials: M
authors.lastname: Jan
authors.forename: Thelma S
authors.initials: TS
authors.lastname: Angeles
authors.forename: Mark S
authors.initials: MS
authors.lastname: Albom
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Mason
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Aimone
authors.forename: Sheryl L
authors.initials: SL
authors.lastname: Meyer
authors.forename: Zeqi
authors.initials: Z
authors.lastname: Huang
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Wells-Knecht
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ator
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Ruggeri
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Dorsey
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D002460:Cell Line; D018360:Crystallography, X-Ray; D004285:Dogs; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C567989:CEP 33779; D011725:Pyridines; D014230:Triazoles; D053614:Janus Kinase 2