YM-16638 ([[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-1,3,4-++ +thiadiazol-2-yl] thio] acetic acid) showed a strong hypocholesterolemic effect in humans and monkeys. To clarify the mechanism of this hypocholesterolemic effect, the action of YM-16638 on cholesterol biosynthesis in the cultured human hepatoma cell line HepG2 and cynomolgus monkey liver was examined. Cholesterol biosynthesis activity derived from [14C]acetic acid, [3H/14C]mevalonic acid or [14C]isopentenyl pyrophosphate substrates was significantly decreased, but not that from [3H]farnesyl pyrophosphate or [3H]squalene substrates in HepG2 cells treated with YM-16638. Simultaneously, treatment of these cells with YM-16638 changed neither the rate of apolipoprotein B synthesis from [35S]methionine nor its secretion. In addition, the activities of hepatic cholesterol biosynthesis enzymes HMG-CoA reductase, mevalonate kinase (MK), isopentenyl pyrophosphate isomerase (IPPI), farnesyl pyrophosphate synthase (FPPS), squalene synthase and squalene epoxidase were measured in monkeys fed a diet supplemented with YM-16638. Among these enzymes, MK, IPPI and FPPS activities in the YM-16638-treated group significantly decreased by 38%, 56% and 30%, respectively, when compared to those from control animals receiving no drug treatment. These results indicate that YM-16638 has the characteristics of a cholesterol biosynthesis inhibitor.

01 Mar 1995·European Journal of PharmacologyQ3 · MEDICINE

Gastric mucosal protection by YM638, a novel leukotriene D4 receptor antagonist, in rats

Q3 · MEDICINE

Article

Author: Takizawa, Kenji ; Kamato, Takeshi ; Takeda, Masaaki ; Nishida, Akito ; Miyata, Keiji

YM638 ([[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl] thio]-1,3,4-thiadiazol-2-yl]thio] acetic acid) is a novel leukotriene D4 receptor antagonist. We investigated the involvement of the leukotriene D4 receptor blocking activity of YM638 in the gastric mucosal protection of this drug in rats. YM638 significantly prevented gastric lesion formation induced by water-immersion restraint stress, indomethacin, absolute ethanol, 0.7 N HCl and the combination of 0.2 N HCl and hemorrhagic shock, with ED50 values of 26.4, 4.1, 4.7, 35.4 and 8.0 mg/kg p.o., respectively. Cetraxate and sofalcone showed inhibitory effects on most of these gastric lesions, but the inhibitory effects of these compounds were much weaker than those of YM638. In contrast, YM638 had no effect on gastric acid secretion and gastric lesion formation in pylorus-ligated rats, or on duodenal lesion formation in cysteamine-administered rats. YM638 competitively antagonized leukotriene D4-induced contraction of the isolated stomach, with a pA2 value of 7.63 +/- 0.18. In anesthetized rats, intravenous YM638 inhibited leukotriene D4-induced aggravation of gastric lesions caused by HCl, and leukotriene D4 and HCl-induced reduction of the potential difference. In addition, oral YM638 significantly increased gastric mucosal blood flow and prevented ethanol-induced increase in gastric vascular permeability. Endogenous prostaglandins, sulfhydryls and nitric oxides were not involved in this inhibitory effect on absolute ethanol-induced gastric lesion. YM638 did not react with the stable free radical 1,1-diphenyl-2-picrylhydrazyl in vitro, indicating that YM638 does not have potential as free radical scavenger. These results suggest that the preventive effect of YM638 on gastric lesions is attributable not only to its leukotriene D4 receptor blocking activity but also to the activation of gastric mucosal defensive mechanisms such as mucosal blood flow and vascular permeability.

01 Jun 1992·Journal of Clinical GastroenterologyQ3 · MEDICINE

Role of Leukotrienes in Gastric Mucosal Injury Induced by Ischemia–Reperfusion in Rats

Q3 · MEDICINE

Article

Author: Kondo, M ; Naito, Y ; Ichikawa, H ; Yoshikawa, T

This study was designed to clarify the role of leukotrienes (LTs) in gastric injury induced by ischemia-reperfusion in rats. Gastric lesions were produced by clamping of the celiac artery and by reoxygenation following clamping. Administration of AA-861, a lipoxygenase inhibitor, significantly inhibited the increase in the total area of the gastric erosions and the increase in thiobarbituric acid-reactive substances in the gastric mucosa. Administration of YM-638, a peptide LT antagonist, showed protective effects similar to AA-861. These results suggest that the protective effects of AA-861 and YM-638 against ischemia-reperfusion-induced gastric injury were due to their antioxidative action.

100 Deals associated with YM-638

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 1	JP	Yamanouchi Pharmaceutical Co. Ltd. /Over-the-Counter Phar Bus	-
Hyperlipidemias	Phase 1	JP	Yamanouchi Pharmaceutical Co. Ltd. /Over-the-Counter Phar Bus	-
Hyperlipidemias	Phase 1	-	Astellas Pharma, Inc.	-
Peptic Ulcer	Phase 1	JP	Yamanouchi Pharmaceutical Co. Ltd. /Over-the-Counter Phar Bus	-

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