title: Synthesis and pharmacological evaluation of 5-(4-biphenyl)-3-methyl-4-phenyl-1,2,4-triazole derivatives as a novel class of selective antagonists for the human vasopressin V(1A) receptor.
abstract: A series of 5-(4-biphenyl)-3-methyl-4-phenyl-1,2,4-triazole derivatives were prepared and evaluated as selective antagonists for the human vasopressin V(1A) receptor. The compounds were examined for their affinity to the cloned human V(1A) receptor (hV(1A)) and selectivity vs the cloned human V(2) receptor (hV(2)). By utilizing the structure-activity relationship on 4,4-difluoro-5-methylidene-2,3,4,5-tetrahydrobenzazepine derivatives as dual antagonists for the V(1A) and V(2) receptors in our previous study, we found that substituting the methoxy group at the 2-position of the 4-phenyl ring with (4-methylpiperazin-1-yl)alkoxy moieties brought about marked improvement of both affinity to hV(1A) and selectivity vs hV(2). Further introduction of a methyl group into the 6-position of the 4-phenyl ring resulted in additional improvement of selectivity. One particular compound, 5-(4-biphenyl)-3-methyl-4-[2-[6-(4-methyl-1-piperazinyl)hexyloxy]phenyl]-1,2,4-triazole (19) showed potent affinity to hV(1A) with a K(i) value of 1.04 nM and high selectivity with a 1700-fold selectivity vs hV(2). We also found marked differences in the affinity of compounds in this series between the human and the rat receptors. Compound 19 was further examined for its V(1A) receptor antagonist activity in rats. As a result, 19 demonstrated antagonist activities toward an arginine vasopressin-induced increase in diastolic blood pressure after intravenous or oral administration and long-lasting oral activity.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, 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: Junko
authors.initials: J
authors.lastname: Tsukada
authors.forename: Atsuo
authors.initials: A
authors.lastname: Tahara
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sakamoto
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Tsukamoto
mesh_terms: D000284:Administration, Oral; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D006801:Humans; D007275:Injections, Intravenous; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D017483:Receptors, Vasopressin / Q000378:metabolism; D013045:Species Specificity; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C458045:5-(4-biphenyl)-3-methyl-4-(2-(6-(4-methyl-1-piperazinyl)hexyloxy)phenyl)-1,2,4-triazole; D065092:Antidiuretic Hormone Receptor Antagonists; D000959:Antihypertensive Agents; D010879:Piperazines; D017483:Receptors, Vasopressin; D014230:Triazoles