Drug Syntheses Beyond the Rule of 5.

Clicks: 20
ID: 36150
2019
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Ranked #110 of 117 articles by views in Chemistry (Weinheim an der Bergstrasse, Germany)

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Abstract
Drugs in 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 semisynthetic 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 macrocyclization in hepatitis C virus protease inhibitors. We conclude that structural simplification, planning of synthetic routes regarding incorporation of stereocenters and macrocylisation, as well as incorporation of structural knowledge and consideration of chameleonic properties in design, should facilitate drug discovery in bRo5 space.
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tyagi2019drugchemistry Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Tyagi, Mohit;Begnini, Fabio;Poongavanam, Vasanthanathan;Doak, Bradley C;Kihlberg, Jan;
Journal Chemistry (Weinheim an der Bergstrasse, Germany)
Year 2019
DOI
10.1002/chem.201902716
URL
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