title: Structure-Based Design and Synthesis of 3-Amino-1,5-dihydro-4H-pyrazolopyridin-4-one Derivatives as Tyrosine Kinase 2 Inhibitors.
abstract: We report herein the discovery and optimization of 3-amino-1,5-dihydro-4H-pyrazolopyridin-4-one TYK2 inhibitors. High-throughput screening against TYK2 and JAK1-3 provided aminoindazole derivative 1 as a hit compound. Scaffold hopping of the aminoindazole core led to the discovery of 3-amino-1,5-dihydro-4H-pyrazolopyridin-4-one derivative 3 as a novel chemotype of TYK2 inhibitors. Interestingly, initial SAR study suggested that this scaffold could have a vertically flipped binding mode, which prompted us to introduce a substituent at the 7-position as a moiety directed toward the solvent-exposed region. Introduction of a 1-methyl-3-pyrazolyl moiety at the 7-position resulted in a dramatic increase in TYK2 inhibitory activity, and further optimization led to the discovery of 20. Compound 20 inhibited IL-23-induced IL-22 production in a rat PD assay, as well as inhibited IL-23 signaling in human PBMC. Furthermore, 20 showed selectivity for IL-23 signaling inhibition against GM-CSF, demonstrating the unique cytokine selectivity of the novel TYK2 inhibitor.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Yogo
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nagamiya
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Seto
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sasaki
authors.affiliation: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited , 40 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Huang
authors.initials: H
authors.lastname: Shih-Chung
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohba
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Norihito
authors.initials: N
authors.lastname: Tokunaga
authors.affiliation: Chemizon , 3F Dongbang Rental Building, 333-1 Sangdaewon-Dong, Jungwon-Gu, Seongnam-Si, Kyunggi-Do 462-120, Korea.
authors.forename: Gil Nam
authors.initials: GN
authors.lastname: Lee
authors.affiliation: Chemizon , 3F Dongbang Rental Building, 333-1 Sangdaewon-Dong, Jungwon-Gu, Seongnam-Si, Kyunggi-Do 462-120, Korea.
authors.forename: Chul Yun
authors.initials: CY
authors.lastname: Rhim
authors.affiliation: Chemizon , 3F Dongbang Rental Building, 333-1 Sangdaewon-Dong, Jungwon-Gu, Seongnam-Si, Kyunggi-Do 462-120, Korea.
authors.forename: Cheol Hwan
authors.initials: CH
authors.lastname: Yoon
authors.affiliation: Chemizon , 3F Dongbang Rental Building, 333-1 Sangdaewon-Dong, Jungwon-Gu, Seongnam-Si, Kyunggi-Do 462-120, Korea.
authors.forename: Suk Young
authors.initials: SY
authors.lastname: Cho
authors.affiliation: Takeda California , 10410 Science Center Drive, San Diego, California 92121, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Skene
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Syunsuke
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yousuke
authors.initials: Y
authors.lastname: Satou
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Kuno
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Miyazaki
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Atsutoshi
authors.initials: A
authors.lastname: Okabe
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Marui
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Aso
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D057166:High-Throughput Screening Assays; D006801:Humans; D053759:Interleukin-23 / Q000494:pharmacology; D007378:Interleukins / Q000096:biosynthesis; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D019169:Jurkat Cells; D008297:Male; D008958:Models, Molecular; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D013329:Structure-Activity Relationship; D053634:TYK2 Kinase / Q000037:antagonists & inhibitors*; D000097043:Interleukin-22
chemical_list: D053759:Interleukin-23; D007378:Interleukins; D053614:Janus Kinase 2; D047428:Protein Kinase Inhibitors; D053634:TYK2 Kinase; D000097043:Interleukin-22; C070139:TYK2 protein, human