title: Beta 1-selective adrenoceptor antagonists: examples of the 2-[4-[3-(substituted amino)-2-hydroxypropoxy]phenyl]imidazole class. 2.
abstract: An attempt to develop a highly cardioselective beta-adrenoceptor antagonist devoid of intrinsic sympathomimetic activity (ISA) focused on exploring structure-activity relationships around (S)-[p-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy] phenyl]-4-(2-thienyl)imidazole. Strategies to reduce or eliminate ISA centered on structural changes that could influence activation of the receptor by the drug itself or by a metabolite. The approaches involved (a) eliminating the acidic imidazole N-H proton, (b) incorporating substituents ortho to the beta-adrenergic blocking side chain, (c) increasing steric bulk around the N-H moiety, (d) decreasing lipophilicity, (e) introducing intramolecular hydrogen bonding involving the imidazole N-H, and (f) displacing the imidazole ring from an activating position by the incorporation of a spacer element. The compounds were investigated in vitro for beta-adrenoceptor antagonism and in vivo for ISA. From these studies, the most successful variation involved the insertion of a spacer between the imidazole and aryl rings. (S)-4-Acetyl-2-[[4-[3-[[2-(3, 4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy]phenyl]methyl] imidazole (S-51) was demonstrated to be highly cardioselective (dose ratio beta 2/beta 1 greater than 9333) and devoid of ISA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Baldwin
authors.forename: M E
authors.initials: ME
authors.lastname: Christy
authors.forename: G H
authors.initials: GH
authors.lastname: Denny
authors.forename: C N
authors.initials: CN
authors.lastname: Habecker
authors.forename: M B
authors.initials: MB
authors.lastname: Freedman
authors.forename: P A
authors.initials: PA
authors.lastname: Lyle
authors.forename: G S
authors.initials: GS
authors.lastname: Ponticello
authors.forename: S L
authors.initials: SL
authors.lastname: Varga
authors.forename: D M
authors.initials: DM
authors.lastname: Gross
authors.forename: C S
authors.initials: CS
authors.lastname: Sweet
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000319:Adrenergic beta-Antagonists; D007093:Imidazoles; D011943:Receptors, Adrenergic, beta