| Literature DB >> 32676146 |
Satheesh Nair1, Sreekantha Ratna Kumar1, Venkatram Reddy Paidi1, Ramesh Sistla1, Durgarao Kantheti1, Subba Rao Polimera1, Soodamani Thangavel1, Amrita Jha Mukherjee1, Mitalee Das1, Rajeev S Bhide2, William J Pitts2, Natesan Murugesan2, Shailesh Dudhgoankar1, Jignesh Nagar1, Siva Subramani1, Debarati Mazumder1, Julie A Carman2, Deborah A Holloway2, Xin Li2, Mark P Fereshteh2, Stefan Ruepp2, Kamalavenkatesh Palanisamy1, T Thanga Mariappan1, Srinivas Maddi1, Ajay Saxena2, Paul Elzinga2, Anjaneya Chimalakonda2, Qian Ruan2, Kaushik Ghosh1, Sucharita Bose1, John Sack2, Chunhong Yan2, Susan E Kiefer2, Dianlin Xie2, John A Newitt2, S Pon Saravanakumar1, Richard A Rampulla2, Joel C Barrish2, Percy H Carter2, John Hynes2.
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.Entities:
Year: 2020 PMID： 32676146 PMCID： PMC7357863 DOI： 10.1021/acsmedchemlett.0c00082
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345