Discovery of MDV6058 (PF-06952229), a selective and potent TGF?R1 inhibitor: Design, synthesis and optimization

Compound 1 is a potent TGF-beta receptor type-1 (TGF beta R1 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...

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Published inBioorganic & medicinal chemistry letters Vol. 75
Main Authors Pujala, Brahmam, Ramachandran, Sreekanth A., Sonawane, Mukesh, Kamble, Maruti M., Panpatil, Dayanand, Adhikari, Swati, Soni, Sanjeev, Subbareddy, Venkata, Shinde, Bharat U., Nayak, Anjan K., Bansal, Chandni, Gupta, Ashu, Mukherjee, Kakoli, Agarwal, Anil K., Guerrero, Javier, Herrera, Francisco J., Bernales, Sebastian, Guha, Mausumee, Chakravarty, Sarvajit, Pham, Son M., Rai, Roopa
Format Journal Article
LanguageEnglish
Published OXFORD Elsevier 01.11.2022
Subjects
Chemistry
Chemistry, Medicinal
Chemistry, Organic
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Physical Sciences
Science & Technology
pSMAD2
PF-06952229
GROWTH
LY2157299
I-RECEPTOR KINASE
TGF?R1
ALK5
Cancer
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Summary:Compound 1 is a potent TGF-beta receptor type-1 (TGF beta R1 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2022.128979