Discovery of 5-Amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Inhibitors of IRAK4
作者： Jongwon Lim , Michael D. Altman , James Baker , Jason D. Brubaker , Hongmin Chen
DOI: 10.1021/ACSMEDCHEMLETT.5B00107
关键词: Kinase 、 Pyrimidine 、 Carboxamide 、 Serine/threonine-specific protein kinase 、 Pyrazole 、 IRAK4 、 Pyrazolopyrimidine 、 Kinase activity 、 Stereochemistry 、 Chemistry
摘要: Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential signal transducer downstream of the IL-1R and TLR superfamily, selective inhibition activity protein represents attractive target for treatment inflammatory diseases. A series 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamides was developed via sequential modifications to 5-position pyrazolopyrimidine ring 3-position pyrazole ring. Replacement substituents responsible poor permeability improvement physical properties guided by cLogD led identification IRAK4 inhibitors with excellent potency, selectivity, pharmacokinetic suitable oral dosing.
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