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

被引：262

作者：

Alex, Alexander ^{[1
]}

Millan, David S. ^{[1
]}

Perez, Manuel ^{[1
]}

Wakenhut, Florian ^{[1
]}

Whitlock, Gavin A. ^{[1
]}

机构：

[1] Pfizer Global Res & Dev, Sandwich Labs, Worldwide Med Chem, Sandwich CT13 9NJ, Kent, England

来源：

MEDCHEMCOMM | 2011年 / 2卷 / 07期

关键词：

MARKETED ORAL-DRUGS; PROTEIN-PROTEIN INTERACTIONS; MOLECULAR-PROPERTIES; MEDICINAL CHEMISTRY; PROPERTY PROFILES; CYCLOSPORINE-A; CONFORMATION; ANTAGONIST; RECEPTOR; BIOAVAILABILITY;

D O I：

10.1039/c1md00093d

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：669 / 674

页数：6

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