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

Satheesh Nair; Sreekantha Ratna Kumar; Venkatram Reddy Paidi; Ramesh Sistla; Durgarao Kantheti; Subba Rao Polimera; Soodamani Thangavel; Amrita Jha Mukherjee; Mitalee Das; Rajeev S Bhide; William J Pitts; Natesan Murugesan; Shailesh Dudhgoankar; Jignesh Nagar; Siva Subramani; Debarati Mazumder; Julie A Carman; Deborah A Holloway; Xin Li; Mark P Fereshteh; Stefan Ruepp; Kamalavenkatesh Palanisamy; T Thanga Mariappan; Srinivas Maddi; Ajay Saxena; Paul Elzinga; Anjaneya Chimalakonda; Qian Ruan; Kaushik Ghosh; Sucharita Bose; John Sack; Chunhong Yan; Susan E Kiefer; Dianlin Xie; John A Newitt; S Pon Saravanakumar; Richard A Rampulla; Joel C Barrish; Percy H Carter; John Hynes Jr

doi:10.1021/acsmedchemlett.0c00082

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

ACS Med Chem Lett. 2020 Jun 10;11(7):1402-1409. doi: 10.1021/acsmedchemlett.0c00082. eCollection 2020 Jul 9.

Authors

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 Hynes Jr²

Affiliations

¹ Biocon Bristol Myers Squibb Research Center, Bangalore 560099, India.
² Research & Development, Bristol Myers Squibb, Route 206 & Province Line Road, Princeton, New Jersey 08543, United States.

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.