title: Introduction of a nitrogen-containing side chain appended on C-10 of cethromycin leads to reduced CYP3A4 inhibition (WO2014049356A1).
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Beijing Institute of Technology, School of Life Science , Beijing 100081 , P R China +86 10 68912140 ; ljhbit@bit.edu.cn.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Liang
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004345:Drug Industry / Q000331:legislation & jurisprudence*; D004347:Drug Interactions; D006801:Humans; D048628:Ketolides / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010330:Patents as Topic; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D048628:Ketolides; C405499:cethromycin
keywords: CYP inhibition; cethromycin; erythromycin; microbial infections; resistant bacteria