C5‐Iminosugar modification of casein kinase 1δ lead 3‐(4‐fluorophenyl)‐5‐isopropyl‐4‐(pyridin‐4‐yl)isoxazole promotes enhanced inhibitor affinity and selectivity. Issue 5 (17th February 2022)

• Record Type: Journal Article
• Authors: von Drathen, Thorsten; Ure, Elizabeth M.; Kirschner, Stefan; Roth, Aileen; Meier, Laura; Woolhouse, Anthony D.; Cameron, Scott A.; Knippschild, Uwe; Peifer, Christian; Luxenburger, Andreas
• Is Part Of: Archiv der Pharmazie. Volume 355:Issue 5(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-02-17
• Subjects: 3, 4‐diaryl‐isoxazole -- chiral kinase inhibitor -- iminosugar -- isoform‐selective -- protein kinase CK1 (formerly known as casein kinase 1) -- ribose pocket; Pharmaceutical chemistry -- Periodicals; Pharmacology -- Periodicals; 615.19
• DOI: 10.1002/ardp.202100497
• Languages: English
• ISSNs: 0365-6233

Abstract

Abstract: 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 (3 R, 4 S )‐ and ethyl (3 S, 4 R )‐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. Abstract : Enantiomerically pure and C5 iminosugar‐modified 3, 4‐diaryl‐isoxazole casein kinase 1δ (CK1δ) inhibitors were synthesized starting from chiral pyrrolidine scaffolds. In vitro assessment of their inhibitory activity toward human CK1δ, ‐ε, and ‐α identified compound (–)‐34 as the most potent CK1δ inhibitor (IC50 (CK1δ) = 1.04 µM), with the 3 S, 4 R ‐configured iminosugar unit inducing a twofold increase in selectivity compared to the lead compound (1 ).