Haviy F, Fitzpatrick T D, Nichols C J, Swenson R E, Bush E N, Diaz G, Nguyen A, Nellans H N, Hoffman D J, Ghanbari H
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064.
J Med Chem. 1992 Oct 16;35(21):3890-4. doi: 10.1021/jm00099a017.
To stabilize leuprolide (1) against chymotrypsin and intestinal degradation several agonists of LHRH (2-12), modified at position 1, 2, or 3 and/or containing N-alpha-methyl at positions 1, 2, or 4, were synthesized by SPPS. These agonists were tested in vitro for (a) rat pituitary LHRH receptor binding, (b) LH release from rat pituitary cells, (c) stability against chymotrypsin, and (d) stability against rat intestinal degradation. The clearances of the compounds in the rat were determined using a RIA. Complete stabilization against chymotrypsin (t1/2) and lumenal degradation (T1/2) was achieved with substitution of NMe-Ser4 in leuprolide; however, with an increase in clearance. Substitution with 1-Nal3 increased both t1/2 and T1/2, while substitution with NAc-Sar1 increased only T1/2. [NAcSar1,NMeSer4,D-Trp6,Pro9NHEt]LHRH (12), the doubly stabilized analogue, was tested in the rat by both iv and id administrations, and its bioavailabilities were measured. No significant improvement in id absorption over leuprolide was observed.
为了使亮丙瑞林（1）对胰凝乳蛋白酶和肠道降解具有稳定性，通过固相肽合成法合成了几种在第1、2或3位进行修饰和/或在第1、2或4位含有N-α-甲基的促黄体生成素释放激素（LHRH）激动剂（2-12）。这些激动剂在体外进行了以下测试：（a）大鼠垂体LHRH受体结合，（b）大鼠垂体细胞释放LH，（c）对胰凝乳蛋白酶的稳定性，以及（d）对大鼠肠道降解的稳定性。使用放射免疫分析法测定了化合物在大鼠体内的清除率。用NMe-Ser4取代亮丙瑞林中的Ser4实现了对胰凝乳蛋白酶（t1/2）和肠腔降解（T1/2）的完全稳定；然而，清除率有所增加。用1-Nal3取代同时增加了t1/2和T1/2，而用NAc-Sar1取代仅增加了T1/2。[NAcSar1，NMeSer4，D-Trp6，Pro9NHEt]LHRH（12），即双稳定类似物，通过静脉注射和皮下注射在大鼠体内进行了测试，并测量了其生物利用度。未观察到皮下吸收比亮丙瑞林有显著改善。
