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The development of analogs of thalidomide was precipitated by the discovery of the anti-angiogenic and anti-inflammatory properties of the drug yielding a new way of fighting cancer as well as some inflammatory diseases after it had been banned in 1961. The problems with thalidomide included; teratogenic side effects, high incidence of other adverse reactions, poor solubility in water and poor absorption from the intestines. In 1998 thalidomide was approved by the US Food and Drug Administration (FDA) for use in newly diagnosed multiple myeloma (MM) under strict regulations. This has led to the development of a number of analogs with fewer side effects and increased potency which include; lenalidomide, (currently marketed), pomalidomide and apremilast (currently marketed), all of which are manufactured by Celgene. ==History== (詳細はGrünenthal). The drug was primarily prescribed as a sedative or hypnotic, but it was also used as an antiemetic and sedative. The drug was banned in 1961 after its teratogenic properties were observed. The problems with thalidomide were, aside from the teratogenic side effects, both high incidence of other adverse reactions along with poor solubility in water and absorption from the intestines.〔(Reversal of Fortune: How a Vilified Drug Became a Life-saving Agent in the "War" Against Cancer - Onco'Zine - The International Oncology Network (November 30, 2013) )〕 Adverse reactions include peripheral neuropathy in large majority of patients, constipation, thromboembolism along with dermatological complications. Four years after thalidomide was withdrawn from the market for its ability to induce severe birth defects, its anti-inflammatory properties were discovered when patients suffering from erythema nodosum leprosum (ENL) used thalidomide as a sedative and it reduced both the clinical signs and symptoms of the disease. Thalidomide was discovered to inhibit tumour necrosis factor-alpha (TNF-α) in 1991. TNF-α is a cytokine produced by macrophages of the immune system, and also a mediator of inflammatory response. Thus the drug is effective against some inflammatory diseases such as ENL. In 1994 Thalidomide was found to have anti-angiogenic activity〔(【引用サイトリンク】title=Thalidomide is an inhibitor of angi... [Proc Natl Acad Sci U S A. 1994] - PubMed - NCBI )〕 and anti-tumor activity〔(【引用サイトリンク】title=Combination oral antiangiogenic therapy with tha... [Br J Cancer. 1999] - PubMed - NCBI )〕 which propelled the initiation of clinical trials for cancer including Multiple Myeloma. The discovery of the anti-inflammatory, anti-angiogenic and anti-tumor activities of thalidomide increased the interest of further research and synthesis of safer analogs.〔(【引用サイトリンク】title=Mechanism of action of thalidomide and 3-aminoth... [Semin Oncol. 2001] - PubMed - NCBI )〕 Lenalidomide is the first analog of thalidomide which is marketed. It is considerably more potent than its parent drug with only two differences at a molecular level, with an added amino group at position 4 of the phthaloyl ring and removal of a carbonyl group from the phthaloyl ring. Development of lenalidomide began in the late 1990s and clinical trials of lenalidomide began in 2000. In October 2001 lenalidomide was granted orphan status for the treatment of MM. In mid-2002 it entered phase II and by early 2003 phase III. In February 2003 FDA granted fast-track status to lenalidomide for the treatment of relapsed or refractory MM.〔 In 2006 it was approved for the treatment of MM along with dexamethasone and in 2007 by European Medicines Agency (EMA). In 2008, phase II trial observed efficacy in treating Non-Hodgkin's lymphoma. Pomalidomide (3-aminothalidomide) was the second thalidomide analog to enter the clinic being more potent than both of its predecessors.〔http://vectorblog.org/2013/04/from-thalidomide-to-pomalyst-better-living-through-chemistry/〕 First reported in 2001, pomalidomide was noted to directly inhibit myeloma cell proliferation and thus inhibiting MM both on the tumor and vascular compartments.〕 This dual activity of Pomalidomide makes it more efficacious than thalidomide ''in vitro'' and ''in vivo''.〔(【引用サイトリンク】title=S-3-Amino-phthalimido-glutarimide inhibits angiog... [Cancer Res. 2002] - PubMed - NCBI )〕 This effect is not related to TNF alpha inhibition since potent TNF alpha inhibitors such as Rolipram and Pentoxifylline did not inhibit myeloma cell growth nor angiogenesis.〔 Up regulation of Interferon gamma, IL-2 and IL-10 have been reported for Pomalidomide and may contribute to its anti-angiogenic and anti-myeloma activities. 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「Development of analogs of thalidomide」の詳細全文を読む スポンサード リンク
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