Otake Kazuya, Azukizawa Satoru, Fukui Masaki, Shibabayashi Michiko, Kamemoto Hikaru, Miike Tomohiro, Kunishiro Kazuyoshi, Kasai Masayasu, Shirahase Hiroaki
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd., Kyoto, Japan.
Chem Pharm Bull (Tokyo). 2011;59(10):1233-42. doi: 10.1248/cpb.59.1233.
Novel 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and (S)-7-(2-{2-[(E)-2-cyclopentylvinyl]-5-methyloxazol-4-yl}ethoxy)-2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (14c) was identified as a peroxisome proliferator-activated receptor (PPAR) α/γ dual agonist. The transactivation activity of 14c was comparable to that of rosiglitazone in human PPARγ (EC50=0.14 µM) and was much higher than in human PPARα (EC50=0.20 µM). In addition, 14c, but not rosiglitazone, showed human protein-tyrosine phosphatase 1B (PTP-1B) inhibitory activity (IC50=1.85 µM). 14c showed about 10-fold stronger hypoglycemic and hypotriglyceridemic effects than rosiglitazone by repeated application for 14 d in male KK-Ay mice. Furthermore, 14c, but not rosiglitazone, increased hepatic peroxisome acyl CoA oxidase activity at 30 mg/kg/d for 7 d in male Syrian hamsters, probably due to its PPARα agonist activity. 14c did not affect plasma volume at 100 mg/kg/d for 14 d in male ICR mice, while rosiglitazone significantly increased it. In conclusion, 14c is a promising candidate for an efficacious and safe anti-diabetic drug with triple actions as a PPARα/γ dual agonist with PTP-1B inhibitory activity.
合成了新型1,2,3,4 - 四氢异喹啉 - 3 - 羧酸衍生物，并且鉴定出(S)-7-(2-{2-[(E)-2-环戊基乙烯基]-5-甲基恶唑-4-基}乙氧基)-2-[(2E,4E)-己二烯酰基]-1,2,3,4 - 四氢异喹啉 - 3 - 羧酸(14c)为过氧化物酶体增殖物激活受体(PPAR)α/γ双重激动剂。14c在人PPARγ中的反式激活活性与罗格列酮相当(EC50 = 0.14 μM)，且远高于人PPARα(EC50 = 0.20 μM)。此外，14c而非罗格列酮具有人蛋白酪氨酸磷酸酶1B(PTP - 1B)抑制活性(IC50 = 1.85 μM)。在雄性KK - Ay小鼠中重复给药14天，14c的降血糖和降甘油三酯作用比罗格列酮强约10倍。此外，在雄性叙利亚仓鼠中，14c而非罗格列酮以30 mg/kg/d的剂量给药7天可增加肝脏过氧化物酶体酰基辅酶A氧化酶活性，这可能归因于其PPARα激动剂活性。在雄性ICR小鼠中，14c以100 mg/kg/d的剂量给药14天不影响血浆容量，而罗格列酮则使其显著增加。总之，14c作为一种具有PTP - 1B抑制活性的PPARα/γ双重激动剂，是一种有潜力的高效安全抗糖尿病药物候选物。
