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Discovery of MDV6058 (PF-06952229), a selective and potent TGFβR1 inhibitor: Design, synthesis and optimization
Bioorganic & Medicinal Chemistry Letters ( IF 2.7 ) Pub Date : 2022-09-08 , DOI: 10.1016/j.bmcl.2022.128979 Brahmam Pujala 1 , Sreekanth A Ramachandran 1 , Mukesh Sonawane 1 , Maruti M Kamble 1 , Dayanand Panpatil 1 , Swati Adhikari 1 , Sanjeev Soni 1 , Venkata Subbareddy 1 , Bharat U Shinde 1 , Anjan K Nayak 1 , Chandni Bansal 1 , Ashu Gupta 1 , Kakoli Mukherjee 1 , Anil K Agarwal 1 , Javier Guerrero 2 , Francisco J Herrera 3 , Sebastian Bernales 3 , Mausumee Guha 4 , Sarvajit Chakravarty 3 , Son M Pham 3 , Roopa Rai 3
中文翻译：
发现 MDV6058 (PF-06952229)，一种选择性强效 TGFβR1 抑制剂：设计、合成和优化
更新日期：2022-09-08
Bioorganic & Medicinal Chemistry Letters ( IF 2.7 ) Pub Date : 2022-09-08 , DOI: 10.1016/j.bmcl.2022.128979 Brahmam Pujala 1 , Sreekanth A Ramachandran 1 , Mukesh Sonawane 1 , Maruti M Kamble 1 , Dayanand Panpatil 1 , Swati Adhikari 1 , Sanjeev Soni 1 , Venkata Subbareddy 1 , Bharat U Shinde 1 , Anjan K Nayak 1 , Chandni Bansal 1 , Ashu Gupta 1 , Kakoli Mukherjee 1 , Anil K Agarwal 1 , Javier Guerrero 2 , Francisco J Herrera 3 , Sebastian Bernales 3 , Mausumee Guha 4 , Sarvajit Chakravarty 3 , Son M Pham 3 , Roopa Rai 3
Affiliation
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Compound 1 is a potent TGF-β receptor type-1 (TGFβR1 or ALK5) inhibitor but is metabolically unstable. A solvent-exposed part of this molecule was used to analogue and modulate cell activity, liver microsome stability and mouse pharmacokinetics. The evolution of SAR that led to the selection of 2 (MDV6058 / PF-06952229) as a preclinical lead compound is described.
中文翻译：
发现 MDV6058 (PF-06952229)，一种选择性强效 TGFβR1 抑制剂：设计、合成和优化
Compound 1是一种有效的 TGF-β 受体 1 型（TGFβR1 或 ALK5）抑制剂，但代谢不稳定。该分子的溶剂暴露部分用于模拟和调节细胞活性、肝微粒体稳定性和小鼠药代动力学。描述了导致选择2 (MDV6058 / PF-06952229) 作为临床前先导化合物的 SAR 演变。
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