Species specificity in the blood cholesterol-lowering effect of YM-16638.
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.
Goto
S
S
Clinical Development Dept., Yamanouchi Pharmaceutical Co., Ltd., Japan.
Shimokawa
T
T
Ugawa
T
T
Hisamichi
N
N
Masuyama
Y
Y
Iizumi
Y
Y
Sato
N
N
Takenaka
T
T
Kodama
T
T
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000097:blood*; D006224:Cricetinae; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D008647:Mesocricetus; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D009929:Organ Size / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D011916:Rats, Inbred F344; D012453:Saimiri; D013045:Species Specificity; D013830:Thiadiazoles / Q000494:pharmacology*
D000924:Anticholesteremic Agents; D013830:Thiadiazoles; C056986:YM 16638; D002784:Cholesterol; D000410:Alanine Transaminase; D008798:Mevalonic Acid