Everolimus

Rapamycin is a polyketide natural product produced by Streptomyces rapamycinicus NRRL5491. The intracellular receptor of 1 is the 12 kDa FK506 binding protein,(FKBP12). The 1–FKBP12 complex is a highly selective and potent inhibitor of mammalian/mechanistic target of rapamy- cin complex 1 (mTORC1) at sub-nanomolar concentrations. Rapamycin is used clinically as an immunosuppressant after organ transplantation (Rapamune) and for the prevention of restenosis after stent insertion for the treatment of coronary heart disease (e.g. Cypher).Semi-synthetic derivatives of Rapamycin including temsirolimus (Torisel) and everolimus (Afinitor) are both approved for the treatment of renal cell carcinoma and other proliferative diseases. Further rapamycin analogues (rapalogs) have shown potential for the treatment of cardiovascular, autoimmune and neurodegenerative diseases.

Rapamycin (sirolimus) is a 31-membered macrocyclic polyketide produced by Streptomyces hygroscopicus. It was discovered on the basis of its antifungal activity and then soon was shown to have potent anti-proliferative/immunosuppressive effects. Rapamycin and its analogues exert their antiproliferative effect by inhibition of mTOR (mammalian target of rapamycin) via FKBP-12-mediated formation of a ternary complex. The powerful anti-proliferative activity of rapamycin have been harnessed clinically to treat organ transplant rejection, and further development has furnished three semisynthetic analogues- temsirolimus (2) and everolimus (34) which are both approved for treatment of advanced renal cancer, and ridaforolimus (35) which is in late stage clinical trial for the treatment of metastatic soft-tissue and bone cancer. (Fig. 6) In contrast to FK506, rapamycin has been the subject of considerable biosynthetic medicinal investigation, and serves as a good example of what is possible with modular polyketide systems.

The initial success with sirolimus had triggered a search of sirolimus analogues that possess similar anti-proliferative effect but lesser adverse effects. Among these analogues, everolimus (a new macrocylic triene derivative), biolimus A9, immunosuppressive agents such as cyclosporine, mycophenolic acid and tacrolimus, which induce G1 arrest leading to reduced proliferation and immune response, have been incorporated in stents. Everolimus is a macrolide antibiotic that possesses the ability to suppress the immune response and cell proliferation leading to prevention of restenosis similar to sirolimus. It possesses greater polarity than sirolimus and hence has better bioavailability and is rapidly absorbed on the arterial wall and attains peak concentration within few hours thereby offering better efficacy. Experimental data have shown that orally administered everolimus inhibits in-stent neointimal formation and significantly promotes neointimal healing. Evorolimus has been found to act at a later stage than the calcineurin inhibitor cyclosporin and tacrolimus.