title: 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.
authors: Medicinal Chemistry Graduate Program, Department of Biomedical & Pharmaceutical Sciences, The University of Montana, Missoula MT 59812, USA.
authors: Nicholas R
authors: NR
authors: Natale
authors: Scott A
authors: SA
authors: Steiger
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000737:chemistry* / Q000378:metabolism; D015220:Calcium Channels / Q000737:chemistry / Q000378:metabolism; D004095:Dihydropyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry*; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D007555:Isoxazoles; C038806:1,4-dihydropyridine