Leone-Bay A, Ho K K, Agarwal R, Baughman R A, Chaudhary K, DeMorin F, Genoble L, McInnes C, Lercara C, Milstein S, O'Toole D, Sarubbi D, Variano B, Paton D R
Emisphere Technologies, Inc., Hawthorne, New York 10532, USA.
J Med Chem. 1996 Jun 21;39(13):2571-8. doi: 10.1021/jm960038f.
A series of N-acetylated, non-alpha, aromatic amino acids was prepared and shown to promote the absorption of recombinant human growth hormone (rhGH) from the gastrointestinal tract. Seventy compounds in this family were tested in vivo in rats. Of the compounds tested, 4-[4-[(2-hydroxybenzoyl)amino]phenyl]butyric acid was identified as a preclinical candidate and was used to demonstrate the oral delivery of rhGH in primates. A significant positive correlation was found between the relative log k' of the delivery agents, as determined by HPLC on an immobilized artificial membrane (IAM) column, and serum rhGH concentrations following oral or colonic dosing in rats. Structure-activity relationships have also been developed on the basis of electronic effects and hydrogen-bonding characteristics of the aromatic amide substituents.
制备了一系列N-乙酰化、非α、芳香族氨基酸，并证明它们可促进重组人生长激素（rhGH）从胃肠道的吸收。该家族中的70种化合物在大鼠体内进行了测试。在所测试的化合物中，4-[4-[(2-羟基苯甲酰基)氨基]苯基]丁酸被确定为临床前候选药物，并用于证明rhGH在灵长类动物中的口服给药。通过固定化人工膜（IAM）柱上的高效液相色谱法测定的给药剂的相对log k'与大鼠口服或结肠给药后的血清rhGH浓度之间发现了显著的正相关。还基于芳香酰胺取代基的电子效应和氢键特征建立了构效关系。
