Discovery of the Potent and Selective Inhaled Janus Kinase 1 Inhibitor AZD4604 and Its Preclinical Characterization

被引：3

作者：

Nilsson, Magnus ^{[1
]}

Berggren, Kristina ^{[1
]}

Berglund, Susanne ^{[1
]}

Cerboni, Silvia ^{[2
]}

Collins, Mia ^{[2
]}

Dahl, Goran ^{[3
]}

Elmqvist, David ^{[4
]}

Grimster, Neil P. ^{[5
]}

Hendrickx, Ramon ^{[6
]}

Johansson, Johan R. ^{[1
]}

Kettle, Jason G. ^{[5
]}

Lepisto, Matti ^{[1
]}

Rhedin, Magdalena ^{[2
]}

Smailagic, Amir ^{[2
]}

Su, Qibin ^{[5
]}

Wennberg, Tiiu ^{[2
]}

Wu, Allan ^{[7
]}

Osterlund, Torben ^{[8
]}

Naessens, Thomas ^{[2
]}

Mitra, Suman ^{[2
]}

机构：

[1] AstraZeneca, BioPharmaceut R&D, Resp & Immunol, Med Chem Res & Early Dev, SE-43183 Gothenburg, Sweden

[2] AstraZeneca, BioPharmaceut R&D, Resp & Immunol, Biosci Res & Early Dev, SE-43183 Gothenburg, Sweden

[3] AstraZeneca, BioPharmaceut R&D, Struct & Biophys Res & Early Dev, Discovery Sci, SE-43183 Gothenburg, Sweden

[4] AstraZeneca, BioPharmaceut R&D, Pharmaceut Sci, Early Prod Dev, SE-43183 Gothenburg, Sweden

[5] AstraZeneca R&D, Oncol R&D, Waltham, MA 02451 USA

[6] AstraZeneca, BioPharmaceut R&D, Res & Early Dev, Resp & Immunol,DMPK, SE-43183 Gothenburg, Sweden

[7] AstraZeneca R&D, Discovery Sci, R&D, Waltham, MA 02451 USA

[8] AstraZeneca, BioPharmaceut R&D, Res & Early Dev, Discovery Sci,Mechanist Biol & Profiling, SE-43183 Gothenburg, Sweden

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年

关键词：

T-CELLS; TISSUE DISTRIBUTION; JAK1; INHIBITORS; IMMUNITY; IDENTIFICATION; MECHANISMS;

D O I：

10.1021/acs.jmedchem.3c00554

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

JAK-STAT cytokines are critical in regulating immunity. Persistent activation of JAK-STAT signaling pathways by cytokines drives chronic inflammatory diseases such as asthma. Herein, we report on the discovery of a highly JAK1-selective, ATP-competitive series of inhibitors having a 1000-fold selectivity over other JAK family members and the approach used to identify compounds suitable for inhaled administration. Ultimately, compound 16 was selected as the clinical candidate, and upon dry powder inhalation, we could demonstrate a high local concentration in the lung as well as low plasma concentrations, suggesting no systemic JAK1 target engagement. Compound 16 has progressed into clinical trials. Using 16, we found JAK1 inhibition to be more efficacious than JAK3 inhibition in IL-4-driven Th2 asthma.

引用

页码：13400 / 13415

页数：16

共 50 条

[1] Discovery of Potent and Selective Pyrazolopyrimidine Janus Kinase 2 Inhibitors
Hanan, Emily J.
van Abbema, Anne
Barrett, Kathy
Blair, Wade S.
Blaney, Jeff
Chang, Christine
Eigenbrot, Charles
Flynn, Sean
Gibbons, Paul
Hurley, Christopher A.
Kenny, Jane R.
Kulagowski, Janusz
Lee, Leslie
Magnuson, Steven R.
Morris, Claire
Murray, Jeremy
Pastor, Richard M.
Rawson, Tom
Siu, Michael
Ultsch, Mark
Zhou, Aihe
Sampath, Deepak
Lyssikatos, Joseph P.
JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (22) : 10090 - 10107
[2] Discovery of C-5 Pyrazole-Substituted Pyrrolopyridine Derivatives as Potent and Selective Inhibitors for Janus Kinase 1
Lang, Jia-Jia
Lv, You
Kobe, Bostjan
Chen, Hongfei
Tan, Yan
Chen, Limei
Wang, Xuechuan
Mi, Pengbing
Zheng, Xing
Lin, Ying-Wu
JOURNAL OF MEDICINAL CHEMISTRY, 2023, 66 (10) : 6725 - 6742
[3] Discovery of Potent and Highly Selective Thienopyridine Janus Kinase 2 Inhibitors
Schenkel, Laurie B.
Huang, Xin
Cheng, Alan
Deak, Holly L.
Doherty, Elizabeth
Emkey, Renee
Gu, Yan
Gunaydin, Hakan
Kim, Joseph L.
Lee, Josie
Loberg, Robert
Olivieri, Philip
Pistillo, Jeanne
Tang, Jin
Wan, Qian
Wang, Hui-Ling
Wang, Shen-Wu
Wells, Mary C.
Wu, Bin
Yu, Violeta
Liu, Liqin
Geuns-Meyer, Stephanie
JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (24) : 8440 - 8450
[4] Discovery of a Potent and Selective Tyrosine Kinase 2 Inhibitor: TAK-279
Leit, Silvana
Greenwood, Jeremy
Carriero, Samantha
Mondal, Sayan
Abel, Robert
Ashwell, Mark
Blanchette, Heather
Boyles, Nicholas A. A.
Cartwright, Mark
Collis, Alan
Feng, Shulu
Ghanakota, Phani
Harriman, Geraldine C. C.
Hosagrahara, Vinayak
Kaila, Neelu
Kapeller, Rosanna
Rafi, Salma B. B.
Romero, Donna L. L.
Tarantino, Paul M. M.
Timaniya, Jignesh
Toms, Angela V. V.
Wester, Ronald T. T.
Westlin, William
Srivastava, Bhaskar
Miao, Wenyan
Tummino, Peter
McElwee, Joshua J. J.
Edmondson, Scott D. D.
Masse, Craig E. E.
JOURNAL OF MEDICINAL CHEMISTRY, 2023, 66 (15) : 10473 - 10496
[5] Initial Solid Tumor Testing (Stage 1) of AZD1480, an Inhibitor of Janus Kinases 1 and 2 by the Pediatric Preclinical Testing Program
Houghton, Peter J.
Kurmasheva, Raushan T.
Lyalin, Dmitry
Maris, John M.
Kolb, E. Anders
Gorlick, Richard
Reynolds, C. Patrick
Kang, Min H.
Keir, Stephen T.
Wu, Jianrong
Smith, Malcolm A.
PEDIATRIC BLOOD & CANCER, 2014, 61 (11) : 1972 - 1979
[6] Discovery of AS-0141, a Potent and Selective Inhibitor of CDC7 Kinase for the Treatment of Solid Cancers
Irie, Takayuki
Asami, Tokiko
Sawa, Ayako
Uno, Yuko
Taniyama, Chika
Funakoshi, Yoko
Masai, Hisao
Sawa, Masaaki
JOURNAL OF MEDICINAL CHEMISTRY, 2021, 64 (19) : 14153 - 14164
[7] Characterization of Selective and Potent JAK1 Inhibitors Intended for the Inhaled Treatment of Asthma
Nilsson, Magnus
Rhedin, Magdalena
Hendrickx, Ramon
Berglund, Susanne
Piras, Antonio
Blomgran, Parmis
Cavallin, Anders
Collins, Mia
Dahl, Goran
Dekkak, Bilel
Ericsson, Therese
Hagberg, Niklas
Holmberg, Ann Aurell
Leffler, Agnes
Lundqvist, Anders J.
Markou, Thomais
Pinkerton, James
Ronnblom, Lars
Siu, Stacey
Taylor, Vanessa
Wennberg, Tiiu
Zervas, Dimitrios
Laurence, Arian D. J.
Mitra, Suman
Belvisi, Maria G.
Birrell, Mark
Borde, Annika
DRUG DESIGN DEVELOPMENT AND THERAPY, 2022, 16 : 2901 - 2917
[8] Discovery and characterization of a novel potent, selective and orally active inhibitor for mammalian ELOVL6
Shimamura, Ken
Nagumo, Akira
Miyamoto, Yasuhisa
Kitazawa, Hidefumi
Kanesaka, Maki
Yoshimoto, Ryo
Aragane, Katsumi
Morita, Naomi
Ohe, Tomoyuki
Takahashi, Toshiyuki
Nagase, Tsuyoshi
Sato, Nagaaki
Tokita, Shigeru
EUROPEAN JOURNAL OF PHARMACOLOGY, 2010, 630 (1-3) : 34 - 41
[9] Generative deep learning enables the discovery of a potent and selective RIPK1 inhibitor
Li, Yueshan
Zhang, Liting
Wang, Yifei
Zou, Jun
Yang, Ruicheng
Luo, Xinling
Wu, Chengyong
Yang, Wei
Tian, Chenyu
Xu, Haixing
Wang, Falu
Yang, Xin
Li, Linli
Yang, Shengyong
NATURE COMMUNICATIONS, 2022, 13 (01)
[10] A Potent and Selective Janus Kinase Inhibitor with a Chiral 3D-Shaped Triquinazine Ring System from Chemical Space
Meier, Kris
Arus-Pous, Josep
Reymond, Jean-Louis
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2021, 60 (04) : 2074 - 2077

← 1 2 3 4 5 →