The association of the isoxazole and dihydropyridine (DHP) ring systems fused at the 4'-isoxazolyl- to the 4-position of the DHP has produced a combination scaffold, the isoxazolyl-DHPs (IDHPs) with unique conformational characteristics. The IDHPs are useful in probing biological activity, as exemplified by our efforts in the fields of voltage gated calcium channel (VGCC) antagonists and inhibitors of the multi-drug resistance (MDR) transporter. A strategically placed methyl group produced a signifcant change at the VGCC, with (R)-(+)-1-phenyl-prop-2-yl (3.7 nM) > phenethyl (22.9 nM) > (S)-(-)-1-phenyl-prop-2-yl (210 nM), a eudismic ratio of 56.7. Branching at the C-5 of the isoxazole produced a 25% increase in MDR binding, and replacing the DHP C-3 ester with a functionalized amide also gave a dramatic increase in binding affinity. Opportunities for combined scaffolds - including examples containing IDHPs - are waiting to be discovered: because new biology is driven by new chemistry.

A critical comparison of methods to prepare sterically hindered 3-aryl isoxazoles containing fused aromatic rings using the nitrile oxide cycloaddition (NOC) reveal that modification of the method of Bode, Hachisu, Matsuura, and Suzuki (BHMS), utilizing either triethylamine as base or sodium enolates of the diketone, ketoester, and ketoamide dipolarophiles, respectively, was the method of choice for this transformation.

No abstract

The 4-Isoxazolyl-dihydropyridines (IDHPs) exhibit inhibition of the multidrug-resistance transporter (MDR-1), and exhibit an SAR distinct from their activity at voltage gated calcium channels (VGCC). Among the four most active IDHPs, three were branched at C-5 of the isoxazole, including the most active analog, 1k.

Isoxazole-1,4-Dihydropyridines (IDHPs) were tethered to Fluorescent moieties using double activation via a lanthanide assisted Weibreb amidation. IDHP-fluorophore conjugate 3c exhibits the highest binding to date for IDHPs at the multidrug-resistance transporter (MDR-1), and IDHP-fluorophore conjugates 3c and 7 distribute selectively in SH-SY5Y cells. A homology model for IDHP binding at MDR-1 is presented which represents our current working hypothesis.