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. 1996 May;118(1):174–178. doi: 10.1111/j.1476-5381.1996.tb15382.x

Species specificity in the blood cholesterol-lowering effect of YM-16638.

S Goto 1, T Shimokawa 1, T Ugawa 1, N Hisamichi 1, Y Masuyama 1, Y Iizumi 1, N Sato 1, T Takenaka 1, T Kodama 1
PMCID: PMC1909480  PMID: 8733592

Abstract

1. The compound YM-16638, [[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl] thio]-1,3,4-thiadiazol-2-yl]thio] acetic acid was developed in a series of in vitro and in vivo studies as a leukotriene D4 receptor antagonist. 2. In a clinical trial as a leukotriene antagonist drug, this compound was found to have a potent serum cholesterol lowering effect in normolipidaemic healthy male volunteers. 3. In the present study, we investigated the serum cholesterol lower effect of this compound in various species of experimental animals. 4. Administration of YM-16638 did not cause a significant decrease in serum total cholesterol (TC) in mice (up to 200 mg kg-1, body weight per day for 28 days), rats (200 mg kg-1 for 15 days) or rabbits (90 mg kg-1 for 18 days). In hamsters, administration of YM-16638 orally or by peritoneal injection at 50 mg kg-1 or more daily for 7 days caused a significant decrease in serum TC and the rate of body weight gain. In monkeys, serum TC did not change in YM-16638-administered squirrel monkeys (50 mg kg-1 daily for 3 weeks), but a significant decrease in serum TC was observed in cynomolgus monkeys (33% decrease at 30 mg kg-1 for 4 weeks) and rhesus monkeys (27% decrease at 30 mg kg-1 for 3 weeks) without any serious decrease in body weight. These results were consistent with those in a phase I study with human subjects. In contrast, serum alanine aminotransferase (ALT) level decreased in all animals after YM-16638 treatment. 5. From these results, we conclude that YM-16638 has a potent hypocholesterolaemic effect, but that this effect if species-specific and is only recognized clearly in human subjects and old-world monkeys.

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Selected References

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  1. Allain C. C., Poon L. S., Chan C. S., Richmond W., Fu P. C. Enzymatic determination of total serum cholesterol. Clin Chem. 1974 Apr;20(4):470–475. [PubMed] [Google Scholar]
  2. Burstein M., Scholnick H. R., Morfin R. Rapid method for the isolation of lipoproteins from human serum by precipitation with polyanions. J Lipid Res. 1970 Nov;11(6):583–595. [PubMed] [Google Scholar]
  3. Dhami M. S., Drangova R., Farkas R., Balazs T., Feuer G. Decreased aminotransferase activity of serum and various tissues in the rat after cefazolin treatment. Clin Chem. 1979 Jul;25(7):1263–1266. [PubMed] [Google Scholar]
  4. Eacho P. I., Foxworthy P. S., Johnson W. D., van Lier R. B. Characterization of liver enlargement induced by compound LY171883 in rats. Fundam Appl Toxicol. 1985 Aug;5(4):794–803. doi: 10.1016/0272-0590(85)90204-0. [DOI] [PubMed] [Google Scholar]
  5. Endo A., Kuroda M., Tanzawa K. Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterolemic activity. FEBS Lett. 1976 Dec 31;72(2):323–326. doi: 10.1016/0014-5793(76)80996-9. [DOI] [PubMed] [Google Scholar]
  6. Endo A. The discovery and development of HMG-CoA reductase inhibitors. J Lipid Res. 1992 Nov;33(11):1569–1582. [PubMed] [Google Scholar]
  7. Feuer G., Balazs T., Farber T. M., Ilse R. G. Effect of cefazolin on aminotransferase activity in the rat. J Toxicol Environ Health. 1981 Mar-Apr;7(3-4):593–606. doi: 10.1080/15287398109530004. [DOI] [PubMed] [Google Scholar]
  8. Fleisch J. H., Rinkema L. E., Haisch K. D., Swanson-Bean D., Goodson T., Ho P. P., Marshall W. S. LY171883, 1-less than 2-hydroxy-3-propyl-4-less than 4-(1H-tetrazol-5-yl) butoxy greater than phenyl greater than ethanone, an orally active leukotriene D4 antagonist. J Pharmacol Exp Ther. 1985 Apr;233(1):148–157. [PubMed] [Google Scholar]
  9. Foxworthy P. S., Perry D. N., Hoover D. M., Eacho P. I. Changes in hepatic lipid metabolism associated with lipid accumulation and its reversal in rats given the peroxisome proliferator LY171883. Toxicol Appl Pharmacol. 1990 Dec;106(3):375–383. doi: 10.1016/0041-008x(90)90334-q. [DOI] [PubMed] [Google Scholar]
  10. Grundy S. M. Cholesterol and coronary heart disease. A new era. JAMA. 1986 Nov 28;256(20):2849–2858. [PubMed] [Google Scholar]
  11. Hoover D. M., Bendele A. M., Hoffman W. P., Foxworthy P. S., Eacho P. I. Effects of chronic treatment with the leukotriene D4 antagonist compound LY171883 on Fischer 344 rats and rhesus monkeys. Fundam Appl Toxicol. 1990 Jan;14(1):123–130. doi: 10.1016/0272-0590(90)90238-f. [DOI] [PubMed] [Google Scholar]
  12. Marshall W. S., Goodson T., Cullinan G. J., Swanson-Bean D., Haisch K. D., Rinkema L. E., Fleisch J. H. Leukotriene receptor antagonists. 1. Synthesis and structure-activity relationships of alkoxyacetophenone derivatives. J Med Chem. 1987 Apr;30(4):682–689. doi: 10.1021/jm00387a018. [DOI] [PubMed] [Google Scholar]
  13. Spady D. K., Dietschy J. M. Dietary saturated triacylglycerols suppress hepatic low density lipoprotein receptor activity in the hamster. Proc Natl Acad Sci U S A. 1985 Jul;82(13):4526–4530. doi: 10.1073/pnas.82.13.4526. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Tomioka K., Garrido R., Stevenson J. S., Abraham W. M. The effect of an orally active leukotriene (LT) antagonist YM-16638 on antigen-induced early and late airway responses in allergic sheep. Prostaglandins Leukot Essent Fatty Acids. 1989 Apr;36(1):43–47. doi: 10.1016/0952-3278(89)90161-0. [DOI] [PubMed] [Google Scholar]
  15. Tomioka K., Yamada T., Mase T., Hara H., Murase K. Pharmacological properties of the orally active leukotriene antagonist [[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propyl]thio]-1,3,4- thiadiazol-2-yl]thio]acetic acid. Arzneimittelforschung. 1988 May;38(5):682–685. [PubMed] [Google Scholar]

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