Nestor J J, Tahilramani R, Ho T L, Goodpasture J C, Vickery B H, Ferrandon P
Institute of Bio-Organic Chemistry, Syntex Research, Palo Alto, California 94304.
J Med Chem. 1992 Oct 16;35(21):3942-8. doi: 10.1021/jm00099a023.
The incorporation of Arg residues into position 6 of gonadotropin releasing hormone antagonists had resulted in compounds with increased in vivo potency but also made these analogues potent mast cell degranulators. We have focused on the substitution of position 8 by hArg(R)2 (NG,NG'-dialkylhomoarginine) substitutions, based on the hypotheses that the Arg-Pro sequence is of major importance for this side effect and that shielding of the charge may be an effective way to block degranulation. Analogues in four series were evaluated: (A) [N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Pal-(3)3,6,Arg5,hArg(R)2(8),D-+ ++Ala10]GnRH, (B) [N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Pal(3)3,6,hArg(R)2(5,8),D-Ala10 ]-GnRH, (C) [N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Pal(3)3,6,hArg(R)2(8),D-Ala10]G nRH, (D) [N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Pal(3)3,D-hArg(R)2(6),hArg(R)2( 8),D-Ala10]GnRH. Although substitution by hArg(Et)2, hArg(Bu), hArg(CH2)3, and hArg(CH2CF3)2 was tested, in each series the hArg(Et)2 residue was superior. Two compounds were considered for clinical evaluation: [N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Pal(3)3,6,hArg(Et)2(8),D-Ala10] GnRH and [N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Pal(3)3,D-hArg(Et)2(6),hArg(Et) 2(8),D- Ala10]GnRH (ganirelix acetate). These compounds had high potency for ovulation suppression and low histamine-releasing potency in vitro (ED50 = 0.6, 0.29 microgram/rat and EC50 = 196, 13 micrograms/mL, respectively). Ganirelix is currently in Phase II clinical trials and appears to be the most potent GnRH antagonist tested in humans (based upon ED50 for 24-h suppression of testosterone levels).
将精氨酸（Arg）残基引入促性腺激素释放激素拮抗剂的第6位，已产生体内效力增强的化合物，但这些类似物也成为有效的肥大细胞脱颗粒剂。基于精氨酸-脯氨酸序列对这种副作用至关重要以及电荷屏蔽可能是阻断脱颗粒的有效方法这两个假设，我们专注于用hArg(R)2（NG,NG'-二烷基高精氨酸）取代第8位。评估了四个系列的类似物：（A）[N-乙酰基-D-萘丙氨酸(2)1,D-对氯苯丙氨酸2,D-哌啶丙氨酸-(3)3,6,精氨酸5,hArg(R)2(8),D-丙氨酸10]促性腺激素释放激素（GnRH），（B）[N-乙酰基-D-萘丙氨酸(2)1,D-对氯苯丙氨酸2,D-哌啶丙氨酸(3)3,6,hArg(R)2(5,8),D-丙氨酸10]-GnRH，（C）[N-乙酰基-D-萘丙氨酸(2)1,D-对氯苯丙氨酸2,D-哌啶丙氨酸(3)3,6,hArg(R)2(8),D-丙氨酸10]GnRH，（D）[N-乙酰基-D-萘丙氨酸(2)1,D-对氯苯丙氨酸2,D-哌啶丙氨酸(3)3,D-hArg(R)2(6),hArg(R)2(8),D-丙氨酸10]GnRH。尽管测试了用hArg(Et)2、hArg(Bu)、hArg(CH2)3和hArg(CH2CF3)2进行取代，但在每个系列中hArg(Et)2残基都是最优的。考虑了两种化合物用于临床评估：[N-乙酰基-D-萘丙氨酸(2)1,D-对氯苯丙氨酸2,D-哌啶丙氨酸(3)3,6,hArg(Et)2(8),D-丙氨酸10]GnRH和[N-乙酰基-D-萘丙氨酸(2)1,D-对氯苯丙氨酸2,D-哌啶丙氨酸(3)3,D-hArg(Et)2(6),hArg(Et)2(8),D-丙氨酸10]GnRH（醋酸加尼瑞克）。这些化合物在体外具有高效的排卵抑制作用和低组胺释放效力（ED50分别为0.6、0.29微克/大鼠，EC50分别为196、13微克/毫升）。加尼瑞克目前处于II期临床试验阶段，似乎是在人体中测试的最有效的GnRH拮抗剂（基于24小时抑制睾酮水平的ED50）。
