title: Synthesis and biological evaluation of (4H-1,2,4-triazol-4-yl)isoquinoline derivatives as selective glycine transporter 1 inhibitors.
abstract: To identify novel glycine transporter 1(GlyT1) inhibitors with greater selectivity relative to GlyT2 and improved aqueous solubility, we synthesized a series of 4H-1,2,4-triazole derivatives with heteroaromatic rings at the 4-position and investigated their structure-activity relationships. Replacement of the 2-fluorophenyl group of lead compound 5 with various aromatic groups led to the identification of 5-(3-biphenyl-4-yl-5-ethyl-4H-1,2,4-triazol-4-yl)isoquinoline (15) with 38-fold selectivity between GlyT1 and GlyT2. 15 also showed improved aqueous solubility and in vivo efficacy on (+)-HA966-induced hyperlocomotion in mice over the lead compound.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. takashi.sugane@astellas.com
authors.forename: Takashi
authors.initials: T
authors.lastname: Sugane
authors.forename: Takahiko
authors.initials: T
authors.lastname: Tobe
authors.forename: Wataru
authors.initials: W
authors.lastname: Hamaguchi
authors.forename: Itsuro
authors.initials: I
authors.lastname: Shimada
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Maeno
authors.forename: Junji
authors.initials: J
authors.lastname: Miyata
authors.forename: Takeshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kimizuka
authors.forename: Takuma
authors.initials: T
authors.lastname: Morita
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sakamoto
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Tsukamoto
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*
chemical_list: C571845:5-(3-biphenyl-4-yl-5-ethyl-4H-1,2,4-triazol-4-yl)isoquinoline; D001713:Biphenyl Compounds; D050487:Glycine Plasma Membrane Transport Proteins; D007546:Isoquinolines; D014230:Triazoles; C045575:1,2,4-triazole; C039109:isoquinoline