title: 3-Amido pyrrolopyrazine JAK kinase inhibitors: development of a JAK3 vs JAK1 selective inhibitor and evaluation in cellular and in vivo models.
abstract: The Janus kinases (JAKs) are involved in multiple signaling networks relevant to inflammatory diseases, and inhibition of one or more members of this class may modulate disease activity or progression. We optimized a new inhibitor scaffold, 3-amido-5-cyclopropylpyrrolopyrazines, to a potent example with reasonable kinome selectivity, including selectivity for JAK3 versus JAK1, and good biopharmaceutical properties. Evaluation of this analogue in cellular and in vivo models confirmed functional selectivity for modulation of a JAK3/JAK1-dependent IL-2 stimulated pathway over a JAK1/JAK2/Tyk2-dependent IL-6 stimulated pathway.
authors.affiliation: Hoffmann-La Roche, 340 Kingsland Street, Nutley, New Jersey 07110, USA. michael.soth@roche.com
authors.forename: Michael
authors.initials: M
authors.lastname: Soth
authors.forename: Johannes C
authors.initials: JC
authors.lastname: Hermann
authors.forename: Calvin
authors.initials: C
authors.lastname: Yee
authors.forename: Muzaffar
authors.initials: M
authors.lastname: Alam
authors.forename: Jim W
authors.initials: JW
authors.lastname: Barnett
authors.forename: Pamela
authors.initials: P
authors.lastname: Berry
authors.forename: Michelle F
authors.initials: MF
authors.lastname: Browner
authors.forename: Karl
authors.initials: K
authors.lastname: Frank
authors.forename: Sandra
authors.initials: S
authors.lastname: Frauchiger
authors.forename: Seth
authors.initials: S
authors.lastname: Harris
authors.forename: Yang
authors.initials: Y
authors.lastname: He
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hekmat-Nejad
authors.forename: Than
authors.initials: T
authors.lastname: Hendricks
authors.forename: Robert
authors.initials: R
authors.lastname: Henningsen
authors.forename: Ramona
authors.initials: R
authors.lastname: Hilgenkamp
authors.forename: Hoangdung
authors.initials: H
authors.lastname: Ho
authors.forename: Ann
authors.initials: A
authors.lastname: Hoffman
authors.forename: Pei-Yuan
authors.initials: PY
authors.lastname: Hsu
authors.forename: Dong-Qing
authors.initials: DQ
authors.lastname: Hu
authors.forename: Andrea
authors.initials: A
authors.lastname: Itano
authors.forename: Saul
authors.initials: S
authors.lastname: Jaime-Figueroa
authors.forename: Alam
authors.initials: A
authors.lastname: Jahangir
authors.forename: Sue
authors.initials: S
authors.lastname: Jin
authors.forename: Andreas
authors.initials: A
authors.lastname: Kuglstatter
authors.forename: Alan K
authors.initials: AK
authors.lastname: Kutach
authors.forename: Cheng
authors.initials: C
authors.lastname: Liao
authors.forename: Stephen
authors.initials: S
authors.lastname: Lynch
authors.forename: John
authors.initials: J
authors.lastname: Menke
authors.forename: Linghao
authors.initials: L
authors.lastname: Niu
authors.forename: Vaishali
authors.initials: V
authors.lastname: Patel
authors.forename: Aruna
authors.initials: A
authors.lastname: Railkar
authors.forename: Douglas
authors.initials: D
authors.lastname: Roy
authors.forename: Ada
authors.initials: A
authors.lastname: Shao
authors.forename: David
authors.initials: D
authors.lastname: Shaw
authors.forename: Sandra
authors.initials: S
authors.lastname: Steiner
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Sun
authors.forename: Seng-Lai
authors.initials: SL
authors.lastname: Tan
authors.forename: Sandra
authors.initials: S
authors.lastname: Wang
authors.forename: Minh Diem
authors.initials: MD
authors.lastname: Vu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018938:Caco-2 Cells; D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D057166:High-Throughput Screening Assays; D006801:Humans; D007376:Interleukin-2 / Q000502:physiology; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D011719:Pyrazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D019947:Receptors, Interleukin-6 / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D003521:Cyclopropanes; D007376:Interleukin-2; D011719:Pyrazines; D011758:Pyrroles; D034741:RNA, Small Interfering; D019947:Receptors, Interleukin-6; D053613:Janus Kinase 1; D053616:Janus Kinase 3