title: Synthesis and evaluation of 1H-pyrrolo[2,3-b]pyridine derivatives as novel immunomodulators targeting Janus kinase 3.
abstract: Janus kinases (JAKs) have been known to play crucial roles in modulating a number of inflammatory and immune mediators. Here, we describe a series of 1H-pyrrolo[2,3-b]pyridine derivatives as novel immunomodulators targeting JAK3 for use in treating immune diseases such as organ transplantation. In the chemical modification of compound 6, the introduction of a carbamoyl group to the C5-position and substitution of a cyclohexylamino group at the C4-position of the 1H-pyrrolo[2,3-b]pyridine ring led to a large increase in JAK3 inhibitory activity. Compound 14c was identified as a potent, moderately selective JAK3 inhibitor, and the immunomodulating effect of 14c on interleukin-2-stimulated T cell proliferation was shown. Docking calculations and WaterMap analysis of the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives were conducted to confirm the substituent effects on JAK3 inhibitory activity.
authors: Drug Discovery Research, Astellas Pharma Inc.
authors: Yutaka
authors: Y
authors: Nakajima
authors: Takashi
authors: T
authors: Tojo
authors: Masataka
authors: M
authors: Morita
authors: Keiko
authors: K
authors: Hatanaka
authors: Shohei
authors: S
authors: Shirakami
authors: Akira
authors: A
authors: Tanaka
authors: Hiroshi
authors: H
authors: Sasaki
authors: Kazuo
authors: K
authors: Nakai
authors: Koichiro
authors: K
authors: Mukoyoshi
authors: Hisao
authors: H
authors: Hamaguchi
authors: Fumie
authors: F
authors: Takahashi
authors: Ayako
authors: A
authors: Moritomo
authors: Yasuyuki
authors: Y
authors: Higashi
authors: Takayuki
authors: T
authors: Inoue
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D056747:Immunomodulation; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology; D008297:Male; D008490:Medical Informatics; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000166:cytology
chemical_list: D011725:Pyridines; C507933:JAK3 protein, human; D053616:Janus Kinase 3