2. Academic Validation
  3. Discovery of a novel series of selective macrocyclic PKCTheta inhibitors

Discovery of a novel series of selective macrocyclic PKCTheta inhibitors

  • Bioorg Med Chem Lett. 2024 Mar 1:100:129630. doi: 10.1016/j.bmcl.2024.129630.
Stefano Crosignani 1,  Sebastien Campos 2,  Claire Bouix-Peter 3,  Craig Harris 3,  Eric Talbot 2,  Haiyang Hu 2,  Shun Wang 2,  John Maclean 2,  Ugo Zanelli 3,  Simon Taylor 2,  Kevin Foote 2,  Feriel Hacini-Rachinel 3,  Edwige Nicodeme 3,  Valerie Julia 3
Affiliations

Affiliations

  • 1 Galderma SA, Av. d'Ouchy 4, 1006 Lausanne, Switzerland. Electronic address: stefano.crosignani@gmail.com.
  • 2 Pharmaron Discovery & Early Development, West Hill Innovation Park, Hertford Road, Hoddesdon, Hertfordshire EN11 9FH, UK.
  • 3 Galderma SA, Av. d'Ouchy 4, 1006 Lausanne, Switzerland.
PMID: 38307441 DOI: 10.1016/j.bmcl.2024.129630
Abstract

A series of macrocyclic PKCθ inhibitors based on a 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hinge binder has been studied. Different aromatic and heteroaromatic substituents have been explored in order to optimize potency, isoform selectivity as well as DMPK properties. The importance of the length of the macrocyclic linker has also been analyzed. In particular, it has been found that methyl substitutions on the linker can have a profound influence on both potency and metabolic stability. Several compounds showing very good profiles, suitable for in vivo testing, are disclosed.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-162234
    PKCTheta Inhibitor
    PKC