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Liang, Jun; van Abbema, Anne; Balazs, Mercedesz; Barrett, Kathy; Berezhkovsky, Leo; Blair, Wade; Chang, Christine; Delarosa, Donnie; DeVoss, Jason; Driscoll, Jim; Eigenbrot, Charles; Ghilardi, Nico; Gibbons, Paul; Halladay, Jason; Johnson, Adam; Kohli, Pawan Bir; Lai, Yingjie; Liu, Yanzhou; Lyssikatos, Joseph; Mantik, Priscilla; Menghrajani, Kapil; Murray, Jeremy; Peng, Ivan; Sambrone, Amy; Shia, Steven; Shin, Young; Smith, Jan; Sohn, Sue; Tsui, Vickie; Ultsch, Mark; Wu, Lawren C; Xiao, Yisong; Yang, Wenqian; Young, Judy; Zhang, Birong; Zhu, Bing-yan; Magnuson, Steven
Journal of medicinal chemistry, 06/2013, Letnik: 56, Številka: 11Journal Article
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.
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Dostop do baze podatkov JCR je dovoljen samo uporabnikom iz Slovenije. Vaš trenutni IP-naslov ni na seznamu dovoljenih za dostop, zato je potrebna avtentikacija z ustreznim računom AAI.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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