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Optimization of Nicotinamides as Potent and Selective IRAK4 Inhibitors with Efficacy in a Murine Model of Psoriasis.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-06-10 , DOI: 10.1021/acsmedchemlett.0c00082 Satheesh Nair 1 , Sreekantha Ratna Kumar 1 , Venkatram Reddy Paidi 1 , Ramesh Sistla 1 , Durgarao Kantheti 1 , Subba Rao Polimera 1 , Soodamani Thangavel 1 , Amrita Jha Mukherjee 1 , Mitalee Das 1 , Rajeev S Bhide 2 , William J Pitts 2 , Natesan Murugesan 2 , Shailesh Dudhgoankar 1 , Jignesh Nagar 1 , Siva Subramani 1 , Debarati Mazumder 1 , Julie A Carman 2 , Deborah A Holloway 2 , Xin Li 2 , Mark P Fereshteh 2 , Stefan Ruepp 2 , Kamalavenkatesh Palanisamy 1 , T Thanga Mariappan 1 , Srinivas Maddi 1 , Ajay Saxena 2 , Paul Elzinga 2 , Anjaneya Chimalakonda 2 , Qian Ruan 2 , Kaushik Ghosh 1 , Sucharita Bose 1 , John Sack 2 , Chunhong Yan 2 , Susan E Kiefer 2 , Dianlin Xie 2 , John A Newitt 2 , S Pon Saravanakumar 1 , Richard A Rampulla 2 , Joel C Barrish 2 , Percy H Carter 2 , John Hynes 2
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-06-10 , DOI: 10.1021/acsmedchemlett.0c00082 Satheesh Nair 1 , Sreekantha Ratna Kumar 1 , Venkatram Reddy Paidi 1 , Ramesh Sistla 1 , Durgarao Kantheti 1 , Subba Rao Polimera 1 , Soodamani Thangavel 1 , Amrita Jha Mukherjee 1 , Mitalee Das 1 , Rajeev S Bhide 2 , William J Pitts 2 , Natesan Murugesan 2 , Shailesh Dudhgoankar 1 , Jignesh Nagar 1 , Siva Subramani 1 , Debarati Mazumder 1 , Julie A Carman 2 , Deborah A Holloway 2 , Xin Li 2 , Mark P Fereshteh 2 , Stefan Ruepp 2 , Kamalavenkatesh Palanisamy 1 , T Thanga Mariappan 1 , Srinivas Maddi 1 , Ajay Saxena 2 , Paul Elzinga 2 , Anjaneya Chimalakonda 2 , Qian Ruan 2 , Kaushik Ghosh 1 , Sucharita Bose 1 , John Sack 2 , Chunhong Yan 2 , Susan E Kiefer 2 , Dianlin Xie 2 , John A Newitt 2 , S Pon Saravanakumar 1 , Richard A Rampulla 2 , Joel C Barrish 2 , Percy H Carter 2 , John Hynes 2
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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.
中文翻译：
在牛皮癣小鼠模型中优化具有效力的烟酰胺作为有效和选择性IRAK4抑制剂。
IRAK4是用于治疗炎症的引人注目的治疗靶标。烟酰胺系列抑制剂的结构导向优化已得到扩展，以探索IRAK4前袋。这导致鉴定出具有改进的效力和选择性的化合物例如12。另外在药代动力学/药效学（PK / PD）模型中显示了12种活性。进一步的优化工作导致了对高激酶组选择性21的鉴定，该蛋白在TLR7驱动的鼠类牛皮癣模型中显示出强大的PD效应和功效。
更新日期：2020-07-09
中文翻译：
在牛皮癣小鼠模型中优化具有效力的烟酰胺作为有效和选择性IRAK4抑制剂。
IRAK4是用于治疗炎症的引人注目的治疗靶标。烟酰胺系列抑制剂的结构导向优化已得到扩展，以探索IRAK4前袋。这导致鉴定出具有改进的效力和选择性的化合物例如12。另外在药代动力学/药效学（PK / PD）模型中显示了12种活性。进一步的优化工作导致了对高激酶组选择性21的鉴定，该蛋白在TLR7驱动的鼠类牛皮癣模型中显示出强大的PD效应和功效。
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