Introduction of a nitrogen-containing side chain appended on C-10 of cethromycin leads to reduced CYP3A4 inhibition (WO2014049356A1)

Abstract

Introduction: Infections caused by antibiotic-resistant bacteria pose an increasing risk for clinical treatment. Macrolide-lincosamide-streptogramin B is becoming increasingly ineffective due to the methylation at the binding site of bacteria. Despite great efforts on the natural product, erythromycin, only one derivative, that is, telithromycin, capable of fighting against resistant bacteria has so far been marketed. However, the 3’-dimethylamino group is readily metabolized to a nitroso group, which would inhibit CYP3A4, a very important metabolic enzyme responsible for nearly half of all marketed drugs.

Areas covered: Modifications at C-10 of erythromycin were seldom reported. This invention disclosed novel ketolides that had a side chain comprising additional nitrogen atoms in place of the original 10-methyl group. Surprisingly, introduction of the side chain at C-10 led to reduced cytochrome inhibition and increased metabolic stability. As a result, the limited ability to inhibit CYP3A4 would relieve the drug–drug interaction and improve the safety of drug co-administration.

Expert opinion: This invention opens a new avenue for future modifications to the erythromycin family. It remains unclear how the side chain effected on reduction of CYP inhibition. To fully identify structure–activity relationships, the MIC data of the derivatives on gram-negative bacteria is desirable.

Keywords:

• cethromycin
• CYP inhibition
• erythromycin
• microbial infections
• resistant bacteria

Declaration of interest

The author was supported by the National Natural Science foundation of China (20602002), the Science Foundation for the Excellent Youth Scholars of Beijing (2013D00 911000002), Excellent Young Scholars Research Fund of BIT (2012YG1606), and Basic Research Foundation of BIT (2012142008). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.