Yuko Mitobe

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.

Development of a selective and potent radioactive ligand for histamine H3 receptors: A compound potentially useful for receptor occupancy studies

Radioligands are powerful tools for examining the pharmacological profiles of chemical leads and thus facilitate drug discovery. In this study, we identified and characterized 3-([1,1,1-(3)H]methyl)-2-(4-{[3-(1-pyrrolidinyl)propyl]oxy} phenyl)-4(3H)-quinazolinone ([(3)H]1) as a potent and selective radioligand for histamine H(3) receptors. Radioligand [(3)H]1 exhibited appreciable specific signal in brain slices prepared from wild-type mice but not from histamine H(3) receptor-deficient mice, demonstrating the specificity and utility of [(3)H]1 as a selective histamine H(3) receptor radioligand for ex-vivo receptor occupancy assays.

Effects of a Novel Y5 Antagonist in Obese Mice: Combination With Food Restriction or Sibutramine

Objective: To further address the function of the Y5 receptor in energy homeostasis, we investigated the effects of a novel spironolactone Y5 antagonist in diet‐induced obese (DIO) mice.

Synthesis and evaluation of structurally constrained quinazolinone derivatives as potent and selective histamine H3 receptor inverse agonists.

A series of structurally constrained derivatives of the potent H 3 inverse agonist 1 was designed, synthesized, and evaluated as histamine H 3 receptor inverse agonists. As a result, the N-cyclobutylpiperidin-4-yloxy group as in 2f was identified as an optimal surrogate structure for the flexible 1-pyrrolidinopropoxy group of 1. Subsequent optimization of the quinazolinone core of 2f revealed that substitution at the 5-position of the quinazolinone ring influences potency. Representative derivatives 5a and 5s showed improved potency in a histamine release assay in rats and a receptor occupancy assay in mice.

Comparison of independent and combined chronic anti-obese effects of NPY Y2 receptor agonist, PYY(3-36), and NPY Y5 receptor antagonist in diet-induced obese mice

Neuropeptide Y (NPY) and its family of peptides are thought to have a major role in the physiological control of energy homeostasis. Among five NPY receptors described, stimulation of the Y2 receptor (Y2R) or inhibition of the Y5 receptor (Y5R) has recently been shown to produce weight-lowering effects in obese rodents. The present study examined and compared the effects of a Y2R agonist, PYY(3-36), and a Y5R antagonist, alone and in combination, on food intake and body weight in diet-induced obese (DIO) mice. Acute intraperitoneal injection of PYY(3-36) dose-dependently reduced spontaneous feeding in lean and DIO mice. In contrast, acute oral administration of the Y5R antagonist had no effect on spontaneous feeding or the anorexigenic effects of PYY(3-36). In a chronic study, subcutaneous infusion of PYY(3-36) (1 mg/kg/day for 14 days) significantly reduced food intake and body weight in DIO mice. The Y5R antagonist (10 mg/kg/day for 14 days, orally) reduced body weight to the same extent as PYY(3-36) without a significant feeding reduction. Combined administration of PYY(3-36) and the Y5R antagonist resulted in a greater body weight reduction than treatment with either agent alone. The combined effects on food intake, body weight, and adiposity are almost the same as a hypothetical sum of the effects of each drug alone. These results illustrate that the combination of a Y2R agonist, PYY(3-36), and a Y5R antagonist resulted in additive effects on body weight and adiposity in DIO mice, suggesting that Y2R stimulation signal and Y5R blockade signal act by distinct pathways.

Discovery of pyridone-containing imidazolines as potent and selective inhibitors of neuropeptide Y Y5 receptor

A series of 2-pyridone-containing imidazoline derivatives was synthesized and evaluated as neuropeptide Y Y5 receptor antagonists. Optimization of the 2-pyridone structure on the 2-position of the imidazoline ring led to identification of 1-(difluoromethyl)-5-[(4S,5S)-4-(4-fluorophenyl)-4-(6-fluoropyridin-3-yl)-5-methyl-4,5-dihydro-1H-imidazol-2-yl]pyridin-2(1H)-one (7m). Compound 7m displayed statistically significant inhibition of food intake in an agonist-induced food intake model in SD rats and no adverse cardiovascular effects in anesthetized dogs. In addition, markedly higher brain penetrability and a lower plasma Occ90 value were observed in P-gp-deficient mdr1a (-/-) mice compared to mdr1a (+/+) mice after oral administration of 7m.

Synthesis, structure–activity relationships, and biological profiles of a dihydrobenzoxathiin class of histamine H3 receptor inverse agonists

A series of novel dihydrobenzoxathiin derivatives was synthesized and evaluated as potent human histamine H(3) receptor inverse agonists. After systematic modification of lead 1a, the potent and selective histamine H(3) inverse agonist 1-(3-{4-[(2S,3S)-8-methoxy-3-methyl-4,4-dioxido-2,3-dihydro-1,4-benzoxathiin-2-yl]phenoxy}propyl)pyrrolidine (5k) was identified. Compound 5k showed good pharmacokinetic profiles and brain penetrability in laboratory animals. After 3mg/kg oral administration of 5k, significant elevation of brain histamine levels was observed in rats where the brain H(3) receptor was fully occupied.