title: Discovery of 4,5-diphenyl-1,2,4-triazole derivatives as a novel class of selective antagonists for the human V(1A) receptor.
abstract: In the search for a novel class of selective antagonists for the human V(1A) receptor, high-throughput screening (HTS) of the Yamanouchi chemical library using CHO cells expressing the cloned human V(1A) (hV(1A)) receptor led to the discovery of 5-(4-biphenyl)-4-(2-methoxyphenyl)-3-methyl-1,2,4-triazole (3) which possessed the novel 4,5-diphenyl-1,2,4-triazole structure. Subsequent structure-activity relationships studies on a series of the 4,5-diphenyl-1,2,4-triazole derivatives related to 3 revealed that the 4,5-diphenyl-1,2,4-triazole structure played an essential role in exerting high affinity for the hV(1A) receptor and that introduction of a basic amine moiety to the methoxy part of the 4-phenyl ring was effective in the improvement of both affinity for the hV(1A) receptor and selectivity versus the hV(2) receptor. Compound 3 and the 2-(morphorino)ethoxy derivative (11b) were shown to be antagonists for the hV(1A) receptor, from their effects on AVP-induced [Ca(2+)](i) response in CHO cells expressing the hV(1A) receptor.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., 21Miyukigaoka, Tsukuba, 305-8585, Ibaraki, Japan. kakefuda@yamanouchi.co.jp
authors.forename: Akio
authors.initials: A
authors.lastname: Kakefuda
authors.forename: Takeshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Takahiko
authors.initials: T
authors.lastname: Tobe
authors.forename: Atsuo
authors.initials: A
authors.lastname: Tahara
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sakamoto
authors.forename: Shin ichi
authors.initials: Si
authors.lastname: Tsukamoto
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D020013:Calcium Signaling / Q000187:drug effects; D006224:Cricetinae; D006801:Humans; D011869:Radioligand Assay; D017483:Receptors, Vasopressin / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014230:Triazoles / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D000959:Antihypertensive Agents; D017483:Receptors, Vasopressin; D014230:Triazoles