4-isoxazolyl-1,4-dihydropyridines: A tale of two scaffolds

Nicholas R. Natale, Scott A. Steiger

Research output: Contribution to journalReview articlepeer-review

7 Scopus citations


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.

Original languageEnglish
Pages (from-to)923-943
Number of pages21
JournalFuture Medicinal Chemistry
Issue number8
StatePublished - May 2014


Dive into the research topics of '4-isoxazolyl-1,4-dihydropyridines: A tale of two scaffolds'. Together they form a unique fingerprint.

Cite this