Non-peptide glycoprotein IIb/IIIa antagonists. 11. Design and in vivo evaluation of 3,4-dihydro-1 (1H)-isoquinolinone-based antagonists and ethyl ester prodrugs.
Non-peptide glycoprotein IIb/IIIa antagonists. 11. Design and in vivo evaluation of 3,4-dihydro-1 (1H)-isoquinolinone-based antagonists and ethyl ester prodrugs.
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DOI：
10.1021/jm9604787
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发表时间：
1996-11
影响因子：
7.3
通讯作者：
J. Hutchinson;J. Cook;K. Brashear;M. Breslin;J. D. Glass;R. Gould;W. Halczenko;M. Holahan;R. Lynch;G. Sitko;M. Stranieri;G. Hartman
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文献类型：
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作者：
J. Hutchinson;J. Cook;K. Brashear;M. Breslin;J. D. Glass;R. Gould;W. Halczenko;M. Holahan;R. Lynch;G. Sitko;M. Stranieri;G. Hartman
描述了一系列口服活性的糖蛋白IIb/IIIa拮抗剂的构效关系，所述糖蛋白IIb/IIIa拮抗剂含有接枝到3，4-二氢-1（1H）-异喹啉酮核上的氮杂环。这些化合物是前体化合物1（L-734，217，[[3（R）-[2-（哌啶-4-基）乙基]-2-氧代哌啶基]乙酰基]-3（R）-甲基-β-丙氨酸）的结构新颖的类似物，其中内酰胺手性中心已被除去。发现4-哌嗪基-和4-哌啶基-取代的3，4-二氢-1（1H）-异喹啉酮对体外效力最佳。此外，在β-氨基酸的3-位的取代增强了效力，其中3-吡啶基和3-乙炔基类似物是制备的最有效的。改善这些化合物的体内特性的尝试集中在物理性质的修饰上。制备酯前药以增加亲脂性并去除拮抗剂的两性离子性质。前药的方法，加上芳基哌嗪末端（pKa =约9.0），提供适度的碱性和相对非极性的化合物。酸性N-[[7-（哌嗪-1-基）-3，4-二氢-1（1H）-氧代异喹啉-2-基]乙酰基]-3（S）-乙炔基-β-丙氨酸，6d（L-767，679）是一种强效纤维蛋白原受体拮抗剂，能够抑制ADP诱导的人凝胶过滤血小板聚集，IC 50为12 nM。尽管根据离体犬试验结果，6d在0.3 mg/kg剂量下具有口服活性，但该化合物的乙酯前药19（L-767，685）在该剂量下的吸收优于6d。口服给药后，酯19在犬体内转化为6d，估计口服全身利用度> 17%（0-8 h，AUC 19 po/AUC 6div）。此外，猴经口给予1 mg/kg剂量的研究表明，19可在给药后2 - 8 h完全抑制ADP诱导的离体血小板聚集，给药后12 h抑制水平保持在40%。该活性水平上级于相同剂量下6天和1天观察到的活性水平。使用来自恒河猴的离体ADP诱导聚集数据（n = 2，0-8 h，使用AUC 19 po/AUC 6div），当以19剂量给药时，6 d的估计全身口服利用度为32%。
The structure-activity relationship of a series of orally active glycoprotein IIb/IIIa antagonists containing a nitrogen heterocycle grafted onto a 3,4-dihydro-1 (1H)-isoquinolinone core is described. These compounds are structurally novel analogs of the progenitor compound 1 (L-734,217,[[3(R)-[2-(piperidin-4-yl)ethyl]-2-oxopiperidinyl ]acetyl]-3(R)- methyl-beta-alanine) in which the lactam chiral center has been removed. The 4-piperazinyl- and 4-piperidinyl-substituted 3,4-dihydro-1(1H)-isoquinolinones were found to be optimal for in vitro potency. In addition, substitution at the 3-position of the beta-amino acid enhanced potency with the 3-pyridyl and 3-ethynyl analogs being the most potent prepared. Attempts to improve the in vivo profile of these compounds focused on modification of the physical properties. Ester prodrugs were prepared to increase the lipophilicity and remove the zwitterionic nature of the antagonists. The prodrug approach, coupled with the arylpiperazine terminus (pKa = approximately 9.0), afforded moderately basic and relatively nonpolar compounds. The acid N-[[7-(piperazin-1-yl)-3,4-dihydro-1(1H)-oxoisoquinolin-2-yl ]acetyl]-3(S)- ethynyl-beta-alanine, 6d (L-767,679), is a potent fibrinogen receptor antagonist able to inhibit the ADP-induced aggregation of human gel-filtered platelets with an IC50 of 12 nM. Although 6d is orally active based on the results of an ex vivo dog assay at 0.3 mg/kg, the ethyl ester prodrug of this compound, 19 (L-767,685), is better absorbed at this dose than 6d. Upon oral dosing, the ester 19 is converted to 6d in vivo in dog with an estimated oral systemic availability of > 17% (0-8 h, AUC19po/AUC6div). In addition, studies in monkey at an oral dose of 1 mg/kg show that 19 affects the complete inhibition of the ex vivo platelet aggregation in response to ADP between 2 and 8 h postdose with the level of inhibition remaining at 40% at 12 h postdose. This level of activity was superior to that observed for 6d and 1 at the same dose. Using ex vivo ADP-induced aggregation data from rhesus monkey (n = 2, 0-8 h using the AUC19po/AUC6div), the estimated systemic oral availability of 6d when dosed as 19 is 32%.