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    • As mentioned above variation of the A

    2023-01-02

    As mentioned above, variation of the A-ring was undertaken in order to improve microsomal stability and kinase selectivity relative to rosmarinic acid sale (). 1-Imidazole-2-carboxamides with substitution at the 4-position (–) were mostly tolerated with 4-cyano-imidazole-2-carboxamide () having comparable inhibitory activity to the unsubstituted imidazole () (). 2-Benzimidazole () was not tolerated likely due to steric constraints of the gatekeeper. The isomeric imidazole () demonstrated the necessity of the intramolecular H-bond network as previously discussed. Unfortunately, the analogs of the A-ring that were tolerated (,,) did not demonstrate improved metabolic stability or improved kinase selectivity compared to the parent compound () (data not shown). Optimization of the methyl sulfonamide in the D-ring was attempted which, based on the model of compound (), provides both a hydrophobic interaction of the methyl group with a hydrophobic pocket as well as a H-bond interaction of the sulfonamide oxygen with Lys619 of the salt bridge (). Urea, amide and carbamate analogs (,,) were unsuccessful in replacing the methyl sulfonamide (). The inability to replace the sulfonamide can be rationalized by the unique three-dimensional presentation of the sulfonamide methyl and oxygens whereas the replacements described (,,) are planar by nature. Ethyl sulfonamide () also decreased potency which was initially explained by the small size of the hydrophobic pocket occupied by the methyl sulfonamide of () in the model. Subsequent crystal data led to a revised model of compound () () in which the sulfonyl oxygen occupies the hydrophobic pocket while the methyl group orients towards Asn728. The revised conformation was still consistent with the compound () potency in that there was insufficient space for the ethyl variant in the floor pocket. The revised model was also consistent with the sulfonyl urea () demonstrating similar inhibitory potency (89nM) relative to the parent compound (). The sulfonyl urea of () should pay an additional desolvation penalty relative to the methyl sulfone of () while only accruing slightly improved interaction energy between the sulfonamide urea NH2 and carbonyl oxygens on Arg727 and Asn728 due to the poor geometry of the putative H-bonds. Another approach explored optimizing the ()-piperidine functionality of the D ring of compound () which provides a unique vector for the methyl sulfonamide. The ()-enantiomer () of the parent compound was not tolerated (IC=210nM) (). The ()-morpholino analog () showed similar enzymatic activity as the parent compound (). The microsomal stability was slightly improved (E(rat)=0.49() vs. 0.72()), however this compound still exhibited suboptimal cell potency (EC=4.7μM). A cocrystal structure of compound () complexed with Mer(I650M) was obtained (), which was in agreement with the interactions observed in the revised model of compound (). It confirmed the hinge interactions of the amide carbonyl with Met674 and Pro672. The intramolecular H-bond network was confirmed in the co-crystal structure, characterized by amide N-H distances to the 1) imidazole nitrogen of 2.7Ǻ and 2) thiazole nitrogen of 2.6Ǻ. The co-crystal structure also confirmed the methyl sulfonamide interactions including the sulfonamide oxygen H-bond to Lys619 of the salt bridge. The methyl group of the sulfonamide points into a hydrophobic pocket as observed in our revised model. The structure also identified the 4-position of the B-ring phenyl as an appropriate vector to the solvent-accessible region of Mer(I650M). With this structural information in hand, ring systems B and C were further interrogated. While the C-ring participated in the intramolecular H-bond network, there were no other specific interactions observed in the crystal structure of () and modifications were carried out. None of the modifications, however, demonstrated any improvement in the enzymatic potency or the metabolic stability with respect to compound () (data not shown). Based on the MetID result and the prediction for compound (), we were cautiously optimistic that modification of the B-ring system would improve microsomal stability.