title: A structure-activity relationship study of novel phenylacetamides which are sodium channel blockers.
abstract: A structure-activity relationship study of a series of novel Na(+) channel blockers, structurally related to N-[3-(2,6-dimethyl-1-piperidinyl)propyl]-alpha-phenylbenzeneacetamide (1, PD85639) is described. The diphenylacetic acid portion of the molecule was left unchanged throughout the study, while structural features in the amine portion and the amide alkyl linkage of the molecule were modified. The compounds were tested for inhibition of veratridine-stimulated Na(+) influx in CHO cells expressing type IIA Na(+) channels. Several derivatives show a trend toward more potent Na+ channel blockade activity with increasing lipophilicity of the amine portion of the molecule. The presence of a phenyl ring near the amine increases inhibitory potency. A three-carbon spacer between the amide and amine is optimal, and a secondary amide linkage is preferred.
authors.affiliation: Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
authors.forename: I
authors.initials: I
authors.lastname: Roufos
authors.forename: S
authors.initials: S
authors.lastname: Hays
authors.forename: R D
authors.initials: RD
authors.lastname: Schwarz
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D044482:Benzeneacetamides; D016466:CHO Cells; D006224:Cricetinae; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000378:metabolism; D013329:Structure-Activity Relationship; D014701:Veratridine / Q000494:pharmacology
chemical_list: D000081:Acetamides; D044482:Benzeneacetamides; D010880:Piperidines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C081801:PD 85639; D014701:Veratridine; D012964:Sodium