Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space

TLDR

Utilising beyond‑rule‑of‑five chemical space is increasingly important in drug design, yet it often compromises good oral absorption. The study hypothesises that intramolecular hydrogen bonds in drug molecules shield polarity, thereby improving membrane permeability and intestinal absorption. The authors predict the propensity for intramolecular hydrogen bonding by modelling the lowest‑energy gas‑phase conformation of these molecules. NMR evidence confirms intramolecular hydrogen bonding in several beyond‑rule‑of‑five oral drugs, and this bonding modulates apparent lipophilicity, as shown by enhanced intrinsic cell permeability and intestinal absorption in rat and human studies.

Abstract

Utilising 'beyond rule of five' chemical space is becoming increasingly important in drug design, but is usually at odds with good oral absorption. The formation of intramolecular hydrogen bonds in drug molecules is hypothesised to shield polarity facilitating improved membrane permeability and intestinal absorption. NMR based evidence for intramolecular hydrogen bonding in several 'beyond rule of five' oral drugs is described. Furthermore, the propensity for these drugs to form intramolecular hydrogen bonds could be predicted for through modelling the lowest energy conformation in the gas phase. The modulation of apparent lipophilicity through intramolecular hydrogen bonding in these molecules is supported by intrinsic cell permeability and intestinal absorption data in rat and human.