A Double-Blind, Placebo-Controlled, Single Dose and Multiple Ascending Dose, Phase I Study to Evaluate the Safety, Tolerability and Pharmacokinetics of YA-101 in Healthy Subjects

开始日期2023-10-12

申办/合作机构-

100 项与 YA-101 相关的临床结果

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100 项与 YA-101 相关的转化医学

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100 项与 YA-101 相关的专利（医药）

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项与 YA-101 相关的文献（医药）

2011-04-01·Drug Metabolism and Disposition2区 · 医学

Pharmacokinetics, Metabolism, and Disposition of Rivoglitazone, a Novel Peroxisome Proliferator-Activated Receptor γ Agonist, in Rats and Monkeys

2区 · 医学

Article

作者: Takahashi, Makoto ; Izumi, Takashi ; Abe, Koji ; Uchiyama, Minoru ; Tsuruta, Fujiko ; Okazaki, Osamu ; Oguchi, Minoru ; Iwabuchi, Haruo ; Koda, Hiroko

The pharmacokinetics, metabolism, and excretion of rivoglitazone [(RS)-5-{4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzyl}-1,3-thiazolidine-2,4-dione monohydrochloride], a novel thiazolidinedione (TZD) peroxisome proliferator-activated receptor γ selective agonist, were evaluated in male F344/DuCrlCrlj rats and cynomolgus monkeys. The total body clearance and volume of distribution of rivoglitazone were low in both animals (0.329-0.333 ml per min/kg and 0.125-0.131 l/kg for rats and 0.310-0.371 ml per min/kg and 0.138-0.166 l/kg for monkeys), and the plasma half-life was 4.55 to 4.84 h for rats and 6.21 to 6.79 h for monkeys. The oral bioavailability was high (>95% in rats and >76.1% in monkeys), and the exposure increased dose proportionally. After administration of [(14)C]rivoglitazone, radioactivity was mainly excreted in feces in rats, whereas radioactivity was excreted in urine and feces with the same ratio in monkeys. Because excreted rivoglitazone in urine and bile was low, metabolism was predicted to be the main contributor to total body clearance. The structures of 20 metabolites (M1-M20) were identified, and 5 initial metabolic pathways were proposed: O-demethylation, TZD ring opening, N-glucuronidation, N-demethylation, and TZD ring hydroxylation. O-Demethylation was the main metabolic pathway in both animals, but N-demethylation and TZD ring hydroxylation were observed only in monkeys. N-Glucuronide (M13) was nonenzymatically hydrolyzed to TZD ring-opened N-glucuronide (M9), and the amount of these metabolites in monkeys was larger than that in rats. In plasma, rivolitazone was observed as the main component in both animals, and O-demethyl-O-sulfate (M11) was observed as the major metabolite in rats but as many minor metabolites in monkeys.

2010-08-01·Journal of Pharmacology and Experimental Therapeutics3区 · 医学

E3710, a New Proton Pump Inhibitor, with a Long-Lasting Inhibitory Effect on Gastric Acid Secretion

3区 · 医学

Article

作者: Miyazawa, Shuhei ; Kawahara, Tetsuya ; Kubota, Atsuhiko ; Terauchi, Hiroki ; Shinoda, Masanobu ; Iida, Daisuke ; Murota, Miki ; Sou, Yasui ; Fujisaki, Hideaki ; Tabata, Yoshikuni ; Watanabe, Nobuhisa ; Kodama, Kotaro ; Kuramochi, Hiroko ; Kato, Hiroshi ; Harada, Hitoshi ; Hirota, Kazuo ; Nagakawa, Junichi ; Ueda, Masato

We have investigated the pharmacology of sodium (R)-2-[4-(2,2-dimethyl-1,3-dioxan-5-yl) methoxy-3,5-dimethylpyridin-2-yl]methylsulfinyl-1H-benzimidazol (E3710), a new proton pump inhibitor (PPI), and its effect on gastric acid secretion. E3710 irreversibly inhibited H(+),K(+)-ATPase activity in pig gastric vesicles with an acidic internal environment with an IC(50) of 0.28 microM. Administration of E3710 (0.1, 0.2, 0.4, and 0.8 mg/kg; n = 6) intraduodenally in a gastric fistula model in dogs inhibited histamine-stimulated gastric acid secretion at 0 to 2 and 24 to 26 h after administration with ED(50) values of 0.18 and 0.22 mg/kg, respectively. The inhibition by E3710 was 2.3 times more potent than that of another representative PPI, esomeprazole (0.2, 0.4, 0.8, and 1.6 mg/kg; n = 6) at 0 to 2 h after administration (ED(50) = 0.40 mg/kg) and 2.8 times more potent at 24 to 26 h (ED(50) = 0.71 mg/kg). In the gastric fistula dogs, the intragastric pH was >or=4 for 17% (n = 27) of a 24-h period with vehicle alone, but when E3710 was administered, at 0.2 (n = 4), 0.4 (n = 8), and 0.8 mg/kg (n = 5), the pH was >or=4 for 40, 79, and 88% of a day, respectively. The corresponding values for esomeprazole at 0.8 (n = 4) and 1.6 mg/kg (n = 8) were 55 and 59%, respectively. In a crossover study with vehicle, E3710 at 0.4 mg/kg and esomeprazole at 1.6 mg/kg (n = 6), E3710 increased the intragastric pH to >4 for 82% of a day compared with 61% of a day with esomeprazole. These results show that E3710 is a long-acting inhibitor of gastric acid secretion and a promising novel therapy for acid-related diseases, such as gastroesophageal reflux disease.

2009-02-01·Journal of Pharmacology and Experimental Therapeutics3区 · 医学

N-(2-Hydroxyethyl)-N,2-dimethyl-8-{[(4R)-5-methyl-3,4-dihydro-2H-chromen-4-yl]amino}imidazo[1,2-a]pyridine-6-carboxamide (PF-03716556), a Novel, Potent, and Selective Acid Pump Antagonist for the Treatment of Gastroesophageal Reflux Disease

3区 · 医学

Article

作者: Hirao, Akiko ; Kato, Teruhisa ; Sakakibara, Minoru ; Aihara, Takeshi ; Mori, Hiroki ; Taniguchi, Yasuhito ; Ochi, Yasuo ; Takahashi, Nobuyuki ; Kurebayashi, Yoichi ; Ohshiro, Hiroyuki ; Tonai-Kachi, Hiroko

Inhibition of H(+),K(+)-ATPase is accepted as the most effective way of controlling gastric acid secretion. However, current acid suppressant therapy for gastroesophageal reflux disease, using histamine H(2) receptor antagonists and proton pump inhibitors, does not fully meet the needs of all patients because of their mechanism of action. This study sought to characterize the in vitro and in vivo pharmacology of a novel acid pump antagonist, N-(2-Hydroxyethyl)-N,2-dimethyl-8-{[(4R)-5-methyl-3,4-dihydro-2H-chromen-4-yl]amino}imidazo[1,2-a]pyridine-6-carboxamide (PF-03716556), and to compare it with other acid suppressants. Porcine, canine, and human recombinant gastric H(+),K(+)-ATPase activities were measured by ion-leaky and ion-tight assay. The affinities for a range of receptors, ion channels, and enzymes were determined to analyze selectivity profile. Acid secretion in Ghosh-Schild rats and Heidenhain pouch dogs were measured by titrating perfusate and gastric juice samples. PF-03716556 demonstrated 3-fold greater inhibitory activity than 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine (revaprazan), the only acid pump antagonist that has been available on the market, in ion-tight assay. The compound did not display any species differences, exhibiting highly selective profile including the canine kidney Na(+),K(+)-ATPase. Kinetics experiments revealed that PF-03716556 has a competitive and reversible mode of action. More rapid onset of action than 5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]-sulfinyl}-benzimidazole (omeprazole) and 3-fold greater potency than revaprazan were observed in Ghosh-Schild rats and Heidenhain pouch dogs. PF-03716556, a novel acid pump antagonist, could improve upon or even replace current pharmacological treatment for gastroesophageal reflux disease.

100 项与 YA-101 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
多系统萎缩	临床1期	澳大利亚	Yoda Pharmaceuticals, Inc.初创企业	2023-10-12
阿尔茨海默症	临床前	-	Yoda Pharmaceuticals, Inc.初创企业	2023-03-02
精神分裂症	临床前	-	Yoda Pharmaceuticals, Inc.初创企业	2023-03-02