title: Synthesis, structure-activity relationships, and biological profiles of a quinazolinone class of histamine H3 receptor inverse agonists.
abstract: A new series of quinazolinone derivatives was synthesized and evaluated as nonimidazole H 3 receptor inverse agonists. 2-Methyl-3-(4-[[3-(1-pyrrolidinyl)propyl]oxy]phenyl)-5-(trifluoromethyl)-4(3 H)-quinazolinone ( 1) was identified as a promising derivative for further evaluation following optimization of key parameters. Compound 1 has potent H 3 inverse agonist activity and excellent selectivity over other histamine receptor subtypes and a panel of 115 unrelated diverse binding sites. Compound 1 also shows satisfactory pharmacokinetic profiles and brain penetrability in laboratory animals. Two hours after oral administration of 30 mg/kg of 1 to SD rats, significant elevation of brain histamine levels was observed where the brain H 3 receptor was highly occupied (>90%). On the basis of species differences in P-glycoprotein (P-gp) susceptibility of 1 between human and rodent P-gps, the observed rodent brain permeability of 1 is significantly limited by P-gp mediated efflux in rodents, whereas the extent of P-gp mediated efflux in humans should be very small or negligible. The potential of 1 to be an efficacious drug was demonstrated by its excellent brain penetrability and receptor occupancy in P-gp-deficient CF-1 mice.
authors.affiliation: Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co, Ltd, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Nagase
authors.forename: Takashi
authors.initials: T
authors.lastname: Mizutani
authors.forename: Shiho
authors.initials: S
authors.lastname: Ishikawa
authors.forename: Etsuko
authors.initials: E
authors.lastname: Sekino
authors.forename: Takahide
authors.initials: T
authors.lastname: Sasaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujimura
authors.forename: Sayaka
authors.initials: S
authors.lastname: Ito
authors.forename: Yuko
authors.initials: Y
authors.lastname: Mitobe
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Ryo
authors.initials: R
authors.lastname: Yoshimoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tanaka
authors.forename: Akane
authors.initials: A
authors.lastname: Ishihara
authors.forename: Norihiro
authors.initials: N
authors.lastname: Takenaga
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tokita
authors.forename: Takehiro
authors.initials: T
authors.lastname: Fukami
authors.forename: Nagaaki
authors.initials: N
authors.lastname: Sato
mesh_terms: D000588:Amines / Q000737:chemistry; D000818:Animals; D002460:Cell Line; D017442:Histamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D006633:Histamine Antagonists / Q000737:chemistry; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D052999:Quinazolinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D018100:Receptors, Histamine H3 / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D017442:Histamine Agonists; D006633:Histamine Antagonists; D052999:Quinazolinones; D018100:Receptors, Histamine H3