4-Isoxazolyl-1,4-Dihydropyridines: A Tale of Two Scaffolds

Abstract

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.

Dimeric isoxazolyl-1,4-dihydropyridines have enhanced binding at the multi-drug resistance transporter

“…13 This was found to be the case, as 6 was essentially bereft of activity at both the VGCC and mGluR 5 , however a small amount of binding at the MDR-1 was found in the one dose transport inhibition assay (shown in the Supplementry Dt). …”

“…13 In the VGCC arena, several parameters have been found to correlate with biological activity: the conformation of the esters at C-3 and C-5 of the DHP, the sum of the six intra-ring torsion angle in the flattened boat conformation, and the forward presentation of the C-4 aryl group of the DHP. 25 We had earlier postulated that the heterocyclic ring juncture could well adapt divergent conformations dependent on the biomolecular target.…”

“…Dihydropyridines (DHPs) have been under intense study for many years for their ability to inhibit the multidrug transporter. 9,10 More recently we have reported that 4-isoxazolyl-1,4-dihydropyridines (IDHPs) have significant binding at this target, 11–13 and a unique structure activity relationship (SAR) which diverges from their voltage gated calcium channel (VGCC) activity. In our initial study, we found that branching at the C(5) of the isoxazole gave rise to three of the four most efficacious IDHPs at MDR-1.…”

“…This suggested additional binding opportunities in proximity to the putative nucleotide binding domain (NBD) of IDHPs ( vide infra ). 12,13 …”

“…Taking into account previous research the tether’s length is critical, however, the MDR undergoes significant conformational reorganization during the ATP driven efflux. In the apo state used in our previous homology model 12,13 the NBDs reside over 40 Å apart using the mouse P-gp data (pdb accession number 3G5U) (Fig. 2, below), while in the ATP bound state exemplified by Sav1866 (pdb accession number 2ONJ), that distance is reported as 4 Å.…”