Discovery of a novel series of selective macrocyclic PKCTheta inhibitors.

Autor: 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.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2024 Mar 01; Vol. 100, pp. 129630. Date of Electronic Publication: 2024 Feb 01.
DOI: 10.1016/j.bmcl.2024.129630
Abstrakt: 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.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sebastien Campos, Haiyang Yu, Shun Wang, John Maclean, Simon Taylor, Kevin Foote are currently employed by Pharmaron Discovery & Early Development, West Hill Innovation Park, Hertford Road, Hoddesdon, Hertfordshire EN11 9FH. Edwige Nicodeme, Valerie Julia are currently employed by Galderma SA, Av. d'Ouchy 4, 1006 Lausanne, Switzerland.
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Databáze: MEDLINE
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