Department of Medicinal Chemistry Uppsala University SE-751 23 Uppsala SWEDEN.
Department of Cell and Molecular Biology Uppsala University SE-751 23 Uppsala SWEDEN.
ChemistryOpen. 2020 Mar 2;9(3):325-337. doi: 10.1002/open.201900344. eCollection 2020 Mar.
Insulin-regulated aminopeptidase (IRAP) is a new potential macromolecular target for drugs aimed for treatment of cognitive disorders. Inhibition of IRAP by angiotensin IV (Ang IV) improves the memory and learning in rats. The majority of the known IRAP inhibitors are peptidic in character and suffer from poor pharmacokinetic properties. Herein, we present a series of small non-peptide IRAP inhibitors derived from a spiro-oxindole dihydroquinazolinone screening hit (pIC 5.8). The compounds were synthesized either by a simple microwave (MW)-promoted three-component reaction, or by a two-step one-pot procedure. For decoration of the oxindole ring system, rapid MW-assisted Suzuki-Miyaura cross-couplings (1 min) were performed. A small improvement of potency (pIC 6.6 for the most potent compound) and an increased solubility could be achieved. As deduced from computational modelling and MD simulations it is proposed that the -configuration of the spiro-oxindole dihydroquinazolinones accounts for the inhibition of IRAP.
胰岛素调节氨基肽酶（IRAP）是一种新的潜在的大分子药物靶点，旨在治疗认知障碍。血管紧张素 IV（Ang IV）抑制 IRAP 可改善大鼠的记忆和学习能力。大多数已知的 IRAP 抑制剂具有肽性质，且具有较差的药代动力学特性。在此，我们提出了一系列源自螺-氧吲哚二氢喹唑啉酮筛选命中物的小非肽 IRAP 抑制剂（pIC5.8）。这些化合物是通过简单的微波（MW）促进的三组分反应或两步一锅法合成的。为了装饰吲哚环系统，快速 MW 辅助的 Suzuki-Miyaura 交叉偶联（1 分钟）进行。可以实现效力的小幅提高（最有效化合物的 pIC6.6）和溶解度的增加。根据计算建模和 MD 模拟的推断，螺-氧吲哚二氢喹唑啉酮的 -构型解释了对 IRAP 的抑制作用。
