Pop E, Loftsson T, Bodor N
University of Florida, Center for Drug Design and Delivery, J. Hillis Miller Health Center, Gainesville.
Drug Des Deliv. 1990 Mar;5(3):221-37.
A novel series of semisynthetic penicillins was designed and synthesized. The compounds have as an integral part of the molecule a pyridinium <--> dihydropyridine redox system as a substituent at the 6-position. Esters of the dihydropyridine (pro-prodrug) forms of the drugs were expected, because of their pronounced lipophilic character, to easily penetrate biological membranes, including the blood-brain barrier, and to give rise to esters of polar pyridinium ions (prodrug) (via enzymic oxidation of the dihydropyridine moiety). The resulting ions were expected to be rapidly excreted from the periphery, but to be "locked" in the central nervous system; subsequent enzymic cleavage of the ester function was expected to release the free acid-pyridinium salts (drug) in the central nervous system in a sustained manner. The design approach, synthesis, study of some important physicochemical properties, stability determinations and preliminary in vivo distribution and potency evaluations of the novel drugs are described.
设计并合成了一系列新型半合成青霉素。这些化合物分子的一个组成部分是一个吡啶鎓<-->二氢吡啶氧化还原系统，作为6位的取代基。由于药物的二氢吡啶（前体前药）形式具有明显的亲脂性，预计它们能够轻易穿透包括血脑屏障在内的生物膜，并产生极性吡啶鎓离子的酯（前药）（通过二氢吡啶部分的酶促氧化）。预计生成的离子会迅速从外周排出，但会“锁定”在中枢神经系统中；随后酯功能的酶促裂解预计会在中枢神经系统中持续释放游离酸吡啶鎓盐（药物）。描述了新药的设计方法、合成、一些重要物理化学性质的研究、稳定性测定以及初步的体内分布和效力评估。
