Dimeric isoxazolyl-1, 4-dihydropyridines have enhanced binding at the multi-drug resistance transporter. Issue 12 (15th June 2017)

• Record Type: Journal Article
• Authors: Steiger, Scott A.; Li, Chun; Backos, Donald S.; Reigan, Philip; Natale, N.R.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 12(2017)
• Page Start: 3223
• Page End: 3234
• Publication Date: 2017-06-15
• Subjects: Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.04.008
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: A series of dimeric isoxazolyl-1, 4-dihydropyridines (IDHPs) were prepared by click chemistry and examined for their ability to bind the multi-drug resistance transporter (MDR-1), a member of the ATP-binding cassette superfamily (ABC). Eight compounds in the present study exhibited single digit micromolar binding to this efflux transporter. One monomeric IDHP m -Br-1c, possessed submicromolar binding of 510 nM at MDR-1. Three of the dimeric IDHPs possessed <1.5 µM activity, and4b and4c were observed to have superior binding selectivity compared to their corresponding monomers verses the voltage gated calcium channel (VGCC). The dimer with the best combination of activity and selectivity for MDR-1 was analog4c containing an m -Br phenyl moiety in the 3-position of the isoxazole, and a tether with five ethyleneoxy units, referred to herein as Isoxaquidar. Two important controls, mono-triazole5 and pyridine6, also were examined, indicating that the triazole – incorporated as part of the click assembly as a spacer – contributes to MDR-1 binding. Compounds were also assayed at the allosteric site of the mGluR5 receptor, as a GPCR 7TM control, indicating that the p -Br IDHPs4d, 4e and4f with tethers of from n = 2 to 5 ethylenedioxy units, had sub-micromolar affinities with4d being the most efficacious at 193 nM at mGluR5. The results are interpreted using a docking study using a human ABC as our current working hypothesis, and suggest that the distinct SARs emerging for these three divergent classes of biomolecular targets may be tunable, and amenable to the development of further selectivity.