title: Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3.
abstract: Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. As a novel class of immunomodulators targeting JAK3, 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives are promising candidates for treating such diseases. In chemical modification of lead compound 2, the substitution of a cycloalkyl ring for an N-cyanopyridylpiperidine in C4-position was effective for increasing JAK3 inhibitory activity. In addition, modulation of physical properties such as molecular lipophilicity and basicity was important for reducing human ether-a-go-go-related gene (hERG) inhibitory activity. Our optimization study gave compound 31, which exhibited potent JAK3 inhibitory activity as well as weak hERG inhibitory activity. In cellular assay, 31 exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation. In a pharmacokinetic study, good metabolic stability and oral bioavailability of 31 were achieved in rats, dogs, and monkeys. Further, 31 prolonged graft survival in an in vivo rat heterotopic cardiac transplant model.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: yutaka.nakajima@astellas.com.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nakajima
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nakai
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Mukoyoshi
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Hisao
authors.initials: H
authors.lastname: Hamaguchi
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Hatanaka
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sasaki
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Tanaka
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Fumie
authors.initials: F
authors.lastname: Takahashi
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kunikawa
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Usuda
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Moritomo
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Higashi
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Inami
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: shohei.shirakami@astellas.com.
authors.forename: Shohei
authors.initials: S
authors.lastname: Shirakami
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D006084:Graft Rejection / Q000517:prevention & control; D006207:Half-Life; D000882:Haplorhini; D006801:Humans; D007155:Immunologic Factors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D007376:Interleukin-2 / Q000378:metabolism; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000737:chemistry; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016042:Transplantation, Heterotopic
chemical_list: D000577:Amides; D007155:Immunologic Factors; D007376:Interleukin-2; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3; C023666:pyridine
keywords: Docking calculation; Immunomodulator; JAK (Janus kinase); JAK3 inhibitor; Transplant rejection; hERG (human ether-a-go-go-related gene)