Shiho Ishikawa

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.

Discovery of tetrasubstituted imidazolines as potent and selective neuropeptide Y Y5 receptor antagonists: Reduced human ether-a-go-go related gene potassium channel binding affinity and potent antiobesity effect

A series of novel imidazoline derivatives was synthesized and evaluated as neuropeptide Y (NPY) Y5 receptor antagonists. Optimization of previously reported imidazoline leads, 1a and 1b, was attempted by introduction of substituents at the 5-position on the imidazoline ring and modification of the bis(4-fluorphenyl) moiety. A number of potent derivatives without human ether-a-go-go related gene potassium channel (hERG) activity were identified. Selected compounds, including 2a, were shown to have excellent brain and CSF permeability. Compound 2a displayed a suitable pharmacokinetic profile for chronic in vivo studies and potently inhibited D-Trp(34)NPY-induced acute food intake in rats. Oral administration of 2a resulted in a potent reduction of body weight in a diet-induced obese mouse model.

Discovery of Novel Benzoxazinones as Potent and Orally Active Long Chain Fatty Acid Elongase 6 Inhibitors

A series of benzoxazinones was synthesized and evaluated as novel long chain fatty acid elongase 6 (ELOVL6) inhibitors. Exploration of the SAR of the UHTS lead 1a led to the identification of (S)-1y that possesses a unique chiral quarternary center and a pyrazole ring as critical pharmacophore elements. Compound (S)-1y showed potent and selective inhibitory activity toward human ELOVL6 while displaying potent inhibitory activity toward both mouse ELOVL3 and 6 enzymes. Compound (S)-1y showed acceptable pharmacokinetic profiles after oral dosing in mice. Furthermore, (S)-1y significantly suppressed the elongation of target fatty acids in mouse liver at 30 mg/kg oral dosing.

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.

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.

Discovery of substituted 2,4,4-triarylimidazoline derivatives as potent and selective neuropeptide Y Y5 receptor antagonists.

Novel imidazoline derivatives were discovered to be potent neuropeptide Y Y5 receptor antagonists. High-throughput screening of Merck sample collections against the human Y5 receptor resulted in the identification of 2,4,4-triphenylimidazoline (1), which had an IC(50) of 54nM. Subsequent optimization led to the identification of several potent derivatives.