title: Lead optimization of a 4-aminopyridine benzamide scaffold to identify potent, selective, and orally bioavailable TYK2 inhibitors.
abstract: Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12 (IL-12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, compound 37 showed statistically significant knockdown of cytokine interferon-γ (IFNγ), suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo.
authors.affiliation: Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. liang.jun@gene.com
authors.forename: Jun
authors.initials: J
authors.lastname: Liang
authors.forename: Anne
authors.initials: A
authors.lastname: van Abbema
authors.forename: Mercedesz
authors.initials: M
authors.lastname: Balazs
authors.forename: Kathy
authors.initials: K
authors.lastname: Barrett
authors.forename: Leo
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authors.lastname: Berezhkovsky
authors.forename: Wade
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authors.lastname: Blair
authors.forename: Christine
authors.initials: C
authors.lastname: Chang
authors.forename: Donnie
authors.initials: D
authors.lastname: Delarosa
authors.forename: Jason
authors.initials: J
authors.lastname: DeVoss
authors.forename: Jim
authors.initials: J
authors.lastname: Driscoll
authors.forename: Charles
authors.initials: C
authors.lastname: Eigenbrot
authors.forename: Nico
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authors.lastname: Ghilardi
authors.forename: Paul
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authors.lastname: Gibbons
authors.forename: Jason
authors.initials: J
authors.lastname: Halladay
authors.forename: Adam
authors.initials: A
authors.lastname: Johnson
authors.forename: Pawan Bir
authors.initials: PB
authors.lastname: Kohli
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Lai
authors.forename: Yanzhou
authors.initials: Y
authors.lastname: Liu
authors.forename: Joseph
authors.initials: J
authors.lastname: Lyssikatos
authors.forename: Priscilla
authors.initials: P
authors.lastname: Mantik
authors.forename: Kapil
authors.initials: K
authors.lastname: Menghrajani
authors.forename: Jeremy
authors.initials: J
authors.lastname: Murray
authors.forename: Ivan
authors.initials: I
authors.lastname: Peng
authors.forename: Amy
authors.initials: A
authors.lastname: Sambrone
authors.forename: Steven
authors.initials: S
authors.lastname: Shia
authors.forename: Young
authors.initials: Y
authors.lastname: Shin
authors.forename: Jan
authors.initials: J
authors.lastname: Smith
authors.forename: Sue
authors.initials: S
authors.lastname: Sohn
authors.forename: Vickie
authors.initials: V
authors.lastname: Tsui
authors.forename: Mark
authors.initials: M
authors.lastname: Ultsch
authors.forename: Lawren C
authors.initials: LC
authors.lastname: Wu
authors.forename: Yisong
authors.initials: Y
authors.lastname: Xiao
authors.forename: Wenqian
authors.initials: W
authors.lastname: Yang
authors.forename: Judy
authors.initials: J
authors.lastname: Young
authors.forename: Birong
authors.initials: B
authors.lastname: Zhang
authors.forename: Bing-yan
authors.initials: BY
authors.lastname: Zhu
authors.forename: Steven
authors.initials: S
authors.lastname: Magnuson
mesh_terms: D015761:4-Aminopyridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D018360:Crystallography, X-Ray; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018664:Interleukin-12 / Q000378:metabolism; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D051381:Rats; D050797:STAT4 Transcription Factor / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D053634:TYK2 Kinase / Q000037:antagonists & inhibitors*
chemical_list: C582920:2-chloro-4-cyano-6-fluoro-N-(2-(2-fluorocyclopropanecarboxamido)pyridin-4-yl)benzamide; D000631:Aminopyridines; D001549:Benzamides; D050797:STAT4 Transcription Factor; D018664:Interleukin-12; D007371:Interferon-gamma; D015761:4-Aminopyridine; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D053634:TYK2 Kinase