Thalidomide Analogs

The thalidomide analogs CPS49 (30) and CPS11 (31) have been reported to inhibit PI3/AKT signaling in multiple myeloma cells via an anti-angiogenic effect. These compounds are devoid of the teratogenic properties seen with thalidomide and are currently in preclinical development [66]. Compound 30, and to a lesser extent 31, induced a dose-dependent inhibition of proliferation in several multiple myeloma cell lines and reduced phospho-AKT levels [66]. These compounds also inhibited DNA synthesis in cell lines resistant to conventionally used anti-multiple myeloma drugs (e.g. dexamethasone, anthracyclines and melphalan) in a dose-dependent manner. 

Another group of thalidomide analogs, selective cytokine inhibitory drugs (SelCIDs), are phosphodiesterase type 4 inhibitors with potent anti-TNF-a activity but no T-cell co-stimulatory activity. Several SelCIDs are currently under investigation for clinical use. 

Category Immunomodulator Thalidomide analog Half-life 3 hours... 

Lenalidomide was approved recently for the indication of myelodysplastic syndrome where the 5q deletion is present. Since lenalidomide is an analog of thalidomide, all the same precautions must be taken to prevent phocomelia. The time to maximum lenalidomide concentrations occurs 0.5 to 4 hours after the dose. The terminal half-life ranges from 3 to 9 hours. Approximately 65% of lenalidomide is eliminated unchanged in the urine, with clearance exceeding the glomerular filtration rate. To date, no pharmacokinetic studies have been done in patients with renal dysfunction. Lenalidomide is used in the treatment of myelodysplastic syndrome and multiple myeloma. Other side effects are neutropenia, thrombocytopenia, deep vein thrombosis, and pulmonary embolus. 

Significant efforts are currently focused on developing novel agents for multiple myeloma. These include CC5013, a small molecule analog of thalidomide with immunomodulatory effects the proteasome inhibitor PS341 and arsenic trioxide. 

Owing to thalidomide s serious toxicity profile, considerable effort has been expended in the development of analogs. Immunomodulatory derivatives of thalidomide are termed IMiDs. Some IMiDs are much more potent than thalidomide in regulating cytokines and affecting T cell proliferation. CC-5013 (Revimid) is an IMiD that in in vitro and animal studies has been shown to be similar to thalidomide in action but without the sedative effects or teratogenicity. CC-5013 is currently in phase I and II clinical trials for the treatment of myeloma, some myelodysplastic syndromes, and melanoma. Preliminary results show efficacy with decreased toxicity compared with thalidomide. 

Researchers at the biotech company EntreMed, Inc., have recently prepared and tested 2-phthalimidino-glutaric acid analogs of thalidomide and found them to be potent inhibitors of tumor metastasis [28], The key to the success of their synthesis was a resolution via enantioselective ester hydrolysis catalyzed by ChiroCLEC -BL, the CLC form of the protease subtilisin. The authors were able to isolate both enantiomers of the desired product with good optical purity (95% ee) (see Fig. 7). 

Analogy. HiU gives as an example of analogy that the effects of rubella or thalidomide should aUow us to accept slighter but similar evidence with another drug or another viral disease in pregnancy. 

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In 1999, both enantiomers of the fluorinated analog were obtained using LiHMDS and perchloryl fluoride as an electrophilic source of fluorine in 71% yield. After several steps, the enantiomers were separated using chiral high-performance liquid chromatography (HPLC) and biologically evaluated. More recently, the first enantioselective synthesis of both enantiomers of thalidomide was described with the aid of a chiral [N-F]+ reagent obtained by combination of a cinchona alkaloid, dihydroquinine (DHQ), and... 

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