Discovery and Structure Enabled Synthesis of 2,6-Diaminopyrimidin-4-one IRAK4 Inhibitors.
We report the identification and synthesis of a series of aminopyrimidin-4-one IRAK4 inhibitors. Through high throughput screening, an aminopyrimidine hit was identified and modified via structure enabled design to generate a new, potent, and kinase selective pyrimidin-4-one chemotype. This chemotype is exemplified by compound 16, which has potent IRAK4 inhibition activity (IC50 = 27 nM) and excellent kinase selectivity (>100-fold against 99% of 111 tested kinases), and compound 31, which displays potent IRAK4 activity (IC50 = 93 nM) and good rat bioavailability (F = 42%).
Discovery Chemistry, Structural Sciences, Computational Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
W Michael
WM
Seganish
Discovery Chemistry, Structural Sciences, Computational Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Thierry O
TO
Fischmann
Discovery Chemistry, Structural Sciences, Computational Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Brad
B
Sherborne
Discovery Chemistry, Structural Sciences, Computational Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Julius
J
Matasi
Discovery Chemistry, Structural Sciences, Computational Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Brian
B
Lavey
Discovery Chemistry, Structural Sciences, Computational Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
William T
WT
McElroy
Discovery Chemistry, Structural Sciences, Computational Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Deen
D
Tulshian
Discovery Chemistry, Structural Sciences, Computational Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
James
J
Tata
Discovery Chemistry, Structural Sciences, Computational Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Christopher
C
Sondey
Discovery Chemistry, Structural Sciences, Computational Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Charles G
CG
Garlisi
Discovery Chemistry, Structural Sciences, Computational Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Kristine
K
Devito
Discovery Chemistry, Structural Sciences, Computational Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
James
J
Fossetta
Discovery Chemistry, Structural Sciences, Computational Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Daniel
D
Lundell
Discovery Chemistry, Structural Sciences, Computational Chemistry, In Vitro Pharmacology, and Respiratory and Immunology, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Xiaoda
X
Niu
IRAK4; inflammation; kinase inhibitor; structure-based drug design