Synthesis, structure-activity relationships, and biological profiles of a quinazolinone class of histamine H3 receptor inverse agonists.
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.
Nagase
Tsuyoshi
T
Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co, Ltd, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan.
Mizutani
Takashi
T
Ishikawa
Shiho
S
Sekino
Etsuko
E
Sasaki
Takahide
T
Fujimura
Takashi
T
Ito
Sayaka
S
Mitobe
Yuko
Y
Miyamoto
Yasuhisa
Y
Yoshimoto
Ryo
R
Tanaka
Takeshi
T
Ishihara
Akane
A
Takenaga
Norihiro
N
Tokita
Shigeru
S
Fukami
Takehiro
T
Sato
Nagaaki
N
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
D000588:Amines; D017442:Histamine Agonists; D006633:Histamine Antagonists; D052999:Quinazolinones; D018100:Receptors, Histamine H3