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Discovery of a novel series of selective macrocyclic PKCTheta inhibitors.
Crosignani, Stefano; Campos, Sebastien; Bouix-Peter, Claire; Harris, Craig; Talbot, Eric; Hu, Haiyang; Wang, Shun; Maclean, John; Zanelli, Ugo; Taylor, Simon; Foote, Kevin; Hacini-Rachinel, Feriel; Nicodeme, Edwige; Julia, Valerie.
Affiliation
  • Crosignani S; Galderma SA, Av. d'Ouchy 4, 1006 Lausanne, Switzerland. Electronic address: stefano.crosignani@gmail.com.
  • Campos S; Pharmaron Discovery & Early Development, West Hill Innovation Park, Hertford Road, Hoddesdon, Hertfordshire EN11 9FH, UK.
  • Bouix-Peter C; Galderma SA, Av. d'Ouchy 4, 1006 Lausanne, Switzerland.
  • Harris C; Galderma SA, Av. d'Ouchy 4, 1006 Lausanne, Switzerland.
  • Talbot E; Pharmaron Discovery & Early Development, West Hill Innovation Park, Hertford Road, Hoddesdon, Hertfordshire EN11 9FH, UK.
  • Hu H; Pharmaron Discovery & Early Development, West Hill Innovation Park, Hertford Road, Hoddesdon, Hertfordshire EN11 9FH, UK.
  • Wang S; Pharmaron Discovery & Early Development, West Hill Innovation Park, Hertford Road, Hoddesdon, Hertfordshire EN11 9FH, UK.
  • Maclean J; Pharmaron Discovery & Early Development, West Hill Innovation Park, Hertford Road, Hoddesdon, Hertfordshire EN11 9FH, UK.
  • Zanelli U; Galderma SA, Av. d'Ouchy 4, 1006 Lausanne, Switzerland.
  • Taylor S; Pharmaron Discovery & Early Development, West Hill Innovation Park, Hertford Road, Hoddesdon, Hertfordshire EN11 9FH, UK.
  • Foote K; Pharmaron Discovery & Early Development, West Hill Innovation Park, Hertford Road, Hoddesdon, Hertfordshire EN11 9FH, UK.
  • Hacini-Rachinel F; Galderma SA, Av. d'Ouchy 4, 1006 Lausanne, Switzerland.
  • Nicodeme E; Galderma SA, Av. d'Ouchy 4, 1006 Lausanne, Switzerland.
  • Julia V; Galderma SA, Av. d'Ouchy 4, 1006 Lausanne, Switzerland.
Bioorg Med Chem Lett ; 100: 129630, 2024 Mar 01.
Article in En | MEDLINE | ID: mdl-38307441
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.
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Full text: 1 Database: MEDLINE Language: En Year: 2024 Type: Article
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Full text: 1 Database: MEDLINE Language: En Year: 2024 Type: Article