Erythromycin semi-synthetic derivatives

Kirst HA (1993) Semi-synthetic derivatives of erythromycin. Prog Med Chem 30, 57-88. 

Another synthetic strategy for partially or completely inhibiting intramolecular cyclization of erythromycin to hemiketal (8) and spiroketal (9) is modification of the functional groups that participate in the cyclization reactions. These groups include the C-9 ketone, C-6 hydroxyl, and C-8 proton in addition to the 11,12-diol discussed above. These approaches have led to a variety of semi-synthetic derivatives of erythromycin, some of which have been recently approved by regulatory agencies or are in late stages of clinical trials [12-17],... 

In addition to those described above, many other semi-synthetic derivatives of erythromycin have been prepared [15, 120], although none has yet progressed to commercialization. ER 42859 (20) was selected for clinical study from a series of ll-O-alkylerythromycin-9-oximes although it... 

Although erythromycin produces relatively low serum concentrations, it achieves higher concentrations of antibiotic in several important tissues such as pulmonary and prostate. It also penetrates effectively into cells and achieves concentrations exceeding that in the smrounding fluids. Each of the newer semi-synthetic derivatives has an individualized pharmacokinetic profile that differs from the others. The monographs and reviews cited above for specific compoimds provide numerous details of their individual pharmacokinetic parameters. 

Erythromycin is generally regarded as one of the safest antibiotics available. The largest number of side-effects involve gastrointestinal (GI) problems, including nausea, vomiting, diarrhoea, and abdominal pain [290]. In many cases, these GI effects are sufficiently severe to result in cessation of erythromycin therapy. Consequently, a major objective for the semi-synthetic derivatives has been to substantially reduce the incidence and severity of GI effects. An experimental model has been established whereby the effect of derivatives on gut motility in dogs is measured. This model has been used to select derivatives predicted to show fewer GI effects [139]. However, reliance on such a model presupposes that the prokinetic action is... 

Erythromycin is predominantly used to treat infections caused by susceptible organisms in the respiratory tract, skin and soft tissues, and genital tract [4-6, 295]. Results from some early clinical trials of the new semi-synthetic derivatives have been published within the monographs, summaries and reviews referenced above however, complete coverage of this rapidly growing body of literature is beyond the scope of this chapter. As a general rule, all of the newer derivatives have successfully treated infections that lie within the traditional therapeutic range of erythromycin itself[16, 296, 297]. 

Semi-synthetic derivatives of erythromycin have played an important role in antimicrobial chemotherapy. First generation derivatives such as 2 -esters and acid-addition salts significantly improved the chemical stability and... 

Macrolide antibiotics, in some instances, may be considered as hydroxy acid derivatives. In addition, many of them have carbohydrates attached, often with unique structural features, as illustrated by erythromycin (20).53 Although some of these antibiotics are semi-synthetic, all are derived by a fermentation process where the antibiotic is formed as a secondary metabolite. This approach, of course, alleviates the need to perform complex carbohydrate chemistry (see Chapter 19). 

Cethromycin (ABT-773) 39 (Advanced Life Sciences) had an NDA filed in October 2008 for the treatment of CAP.67 Advanced Life Sciences is also evaluating cethromycin 39 against other respiratory tract infections and in pre-clinical studies as a prophylactic treatment of anthrax post-exposure. Cethromycin 3968 70 is a semi-synthetic ketolide derivative of erythromycin 4071 originally synthesised by Abbott Laboratories,72 which like erythromycin 40, inhibits bacterial protein synthesis through binding to the peptidyl-transferase site of the bacterial 50S ribosomal subunit. Important macrolide antibiotics in clinical use today include erythromycin 40 itself, clarithromycin, azithromycin and, most recently, telithromycin (launched in 2001). 

---