Department of Chemistry-BMC, Uppsala University, Box 576, 75123, Uppsala, Sweden.
Department of Medicinal Chemistry, MIPS, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.
Chemistry. 2020 Jan 2;26(1):49-88. doi: 10.1002/chem.201902716. Epub 2019 Oct 11.
Drugs in the chemical space beyond the rule of 5 (bRo5) can modulate targets with difficult binding sites while retaining cell permeability and oral absorption. Reviewing the syntheses of bRo5 drugs approved since 1990 highlights synthetic chemistry's contribution to drug discovery in this space. Initially, bRo5 drugs were mainly natural products and semi-synthetic derivatives. Later, peptidomimetics and de novo designed compounds, that include up to seven chiral centres and macrocyclic rings became dominant. These drugs are prepared by total synthesis, sometimes by routes of more than 25 steps with stereocentres originating from the chiral pool, or being installed by chiral induction or enzymatic resolution. Interestingly, ring-closing metathesis proved to be the method of choice for macrocyclisation in hepatitis C virus protease inhibitors. We conclude that structural simplification, planning of synthetic routes regarding incorporation of stereocentres and macrocyclisation, as well as incorporation of structural knowledge and consideration of chameleonic properties in design, should facilitate drug discovery in bRo5 space.
超越规则 5（bRo5）的化学空间中的药物可以调节具有难以结合部位的靶标，同时保持细胞通透性和口服吸收。审查自 1990 年以来批准的 bRo5 药物的合成，突出了合成化学在该领域对药物发现的贡献。最初，bRo5 药物主要是天然产物和半合成衍生物。后来，肽模拟物和从头设计的化合物，包括多达七个手性中心和大环，成为主要的药物。这些药物通过全合成制备，有时通过超过 25 步的路线合成，其中手性中心来自手性池，或者通过手性诱导或酶促拆分来安装。有趣的是，闭环复分解反应被证明是丙型肝炎病毒蛋白酶抑制剂中环化的首选方法。我们得出的结论是，结构简化、关于立体中心和大环化的合成路线规划，以及在设计中纳入结构知识和考虑变色龙特性，应该有助于 bRo5 空间中的药物发现。
