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C5-Iminosugar modification of casein kinase 1δ lead 3-(4-fluorophenyl)-5-isopropyl-4-(pyridin-4-yl)isoxazole promotes enhanced inhibitor affinity and selectivity.
von Drathen, Thorsten; Ure, Elizabeth M; Kirschner, Stefan; Roth, Aileen; Meier, Laura; Woolhouse, Anthony D; Cameron, Scott A; Knippschild, Uwe; Peifer, Christian; Luxenburger, Andreas.
Afiliación
  • von Drathen T; Ferrier Research Institute, Victoria University of Wellington, Lower Hutt, New Zealand.
  • Ure EM; Institute of Pharmacy, Christian-Albrechts-University of Kiel, Kiel, Germany.
  • Kirschner S; Ferrier Research Institute, Victoria University of Wellington, Lower Hutt, New Zealand.
  • Roth A; Institute of Pharmacy, Christian-Albrechts-University of Kiel, Kiel, Germany.
  • Meier L; Department of General and Visceral Surgery, Ulm University Hospital, Ulm, Germany.
  • Woolhouse AD; Department of General and Visceral Surgery, Ulm University Hospital, Ulm, Germany.
  • Cameron SA; Ferrier Research Institute, Victoria University of Wellington, Lower Hutt, New Zealand.
  • Knippschild U; Ferrier Research Institute, Victoria University of Wellington, Lower Hutt, New Zealand.
  • Peifer C; Department of General and Visceral Surgery, Ulm University Hospital, Ulm, Germany.
  • Luxenburger A; Institute of Pharmacy, Christian-Albrechts-University of Kiel, Kiel, Germany.
Arch Pharm (Weinheim) ; 355(5): e2100497, 2022 May.
Article en En | MEDLINE | ID: mdl-35174898
The quest for isoform-selective and specific ATP-competitive protein kinase inhibitors is of great interest, as inhibitors with these qualities will come with reduced toxicity and improved efficacy. However, creating such inhibitors is very challenging due to the high molecular similarity of kinases ATP active sites. To achieve selectivity for our casein kinase (CK) 1 inhibitor series, we elected to endow our previous CK1δ-hit, 3-(4-fluorophenyl)-5-isopropyl-4-(pyridin-4-yl)isoxazole (1), with chiral iminosugar scaffolds. These scaffolds were attached to C5 of the isoxazole ring, a position deemed favorable to facilitate binding interactions with the ribose pocket/solvent-open area of the ATP binding pocket of CK1δ. Here, we describe the synthesis of analogs of 1 ((-)-/(+)-34, (-)-/(+)-48), which were prepared in 13 steps from enantiomerically pure ethyl (3R,4S)- and ethyl (3S,4R)-1-benzyl-4-[(tert-butyldimethylsilyl)oxy]-5-oxopyrrolidine-3-carboxylate ((-)-11 and (+)-11), respectively. The synthesis involved the coupling of Weinreb amide-activated chiral pyrrolidine scaffolds with 4- and 2-fluoro-4-picoline and reaction of the resulting 4-picolyl ketone intermediates ((-)-/(+)-40 and (-)-/(+)-44) with 4-fluoro-N-hydroxybenzenecarboximidoyl chloride to form the desired isoxazole ring. The activity of the compounds against human CK1δ, -ε, and -α was assessed in recently optimized in vitro assays. Compound (-)-34 was the most active compound with IC50 values (CK1δ/ε) of 1/8 µM and displayed enhanced selectivity toward CK1δ.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Quinasa Idelta de la Caseína Límite: Humans Idioma: En Revista: Arch Pharm (Weinheim) Año: 2022 Tipo del documento: Article País de afiliación: Nueva Zelanda Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Quinasa Idelta de la Caseína Límite: Humans Idioma: En Revista: Arch Pharm (Weinheim) Año: 2022 Tipo del documento: Article País de afiliación: Nueva Zelanda Pais de publicación: Alemania