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Optimization of Nicotinamides as Potent and Selective IRAK4 Inhibitors with Efficacy in a Murine Model of Psoriasis.

ABSTRACT: IRAK4 is an attractive therapeutic target for the treatment of inflammatory conditions. Structure guided optimization of a nicotinamide series of inhibitors has been expanded to explore the IRAK4 front pocket. This has resulted in the identification of compounds such as 12 with improved potency and selectivity. Additionally 12 demonstrated activity in a pharmacokinetics/pharmacodynamics (PK/PD) model. Further optimization efforts led to the identification of the highly kinome selective 21, which demonstrated a robust PD effect and efficacy in a TLR7 driven model of murine psoriasis.

SUBMITTER: Nair S 

PROVIDER: S-EPMC7357863 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Optimization of Nicotinamides as Potent and Selective IRAK4 Inhibitors with Efficacy in a Murine Model of Psoriasis.

Nair Satheesh S   Kumar Sreekantha Ratna SR   Paidi Venkatram Reddy VR   Sistla Ramesh R   Kantheti Durgarao D   Polimera Subba Rao SR   Thangavel Soodamani S   Mukherjee Amrita Jha AJ   Das Mitalee M   Bhide Rajeev S RS   Pitts William J WJ   Murugesan Natesan N   Dudhgoankar Shailesh S   Nagar Jignesh J   Subramani Siva S   Mazumder Debarati D   Carman Julie A JA   Holloway Deborah A DA   Li Xin X   Fereshteh Mark P MP   Ruepp Stefan S   Palanisamy Kamalavenkatesh K   Mariappan T Thanga TT   Maddi Srinivas S   Saxena Ajay A   Elzinga Paul P   Chimalakonda Anjaneya A   Ruan Qian Q   Ghosh Kaushik K   Bose Sucharita S   Sack John J   Yan Chunhong C   Kiefer Susan E SE   Xie Dianlin D   Newitt John A JA   Saravanakumar S Pon SP   Rampulla Richard A RA   Barrish Joel C JC   Carter Percy H PH   Hynes John J  

ACS medicinal chemistry letters 20200610 7

IRAK4 is an attractive therapeutic target for the treatment of inflammatory conditions. Structure guided optimization of a nicotinamide series of inhibitors has been expanded to explore the IRAK4 front pocket. This has resulted in the identification of compounds such as <b>12</b> with improved potency and selectivity. Additionally <b>12</b> demonstrated activity in a pharmacokinetics/pharmacodynamics (PK/PD) model. Further optimization efforts led to the identification of the highly kinome selec  ...[more]

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