Macrocyclic Drugs and Clinical Candidates: What Can Medicinal Chemists Learn from Their Properties?
Macrocyclic Drugs and Clinical Candidates: What Can Medicinal Chemists Learn from Their Properties?
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DOI：
10.1021/jm400887j
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发表时间：
2014-01-23
影响因子：
7.3
通讯作者：
Kihlberg, Jan
中科院分区：
文献类型：
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作者：
Giordanetto, Fabrizio;Kihlberg, Jan
大环化合物是解决“困难”目标的理想选择，但我们对它们的细胞渗透性和口服生物利用度的了解有限。对大约100种大环药物和临床候选药物的分析表明，大环主要用于感染性疾病和肿瘤学，大多数属于大环内酯类或环肽类。大量（N = 34）这些大环化合物口服给药，表明口服生物利用度可以在分子量高达和高于1 kDa和极性表面积范围接近250埃时获得（2）。此外，从一组“从头设计”的口服大环化合物在临床研究中的洞察力和环孢菌素A和模型环六肽如何穿过细胞膜的理解可能会在药物发现中释放更广泛的机会。然而，口服大环化合物的数量仍然很低，它们是否是离群值或大环化合物是否会开辟新的口服可药用空间还有待观察。
Macrocycles are ideal in efforts to tackle "difficult" targets, but our understanding of what makes them cell permeable and orally bioavailable is limited. Analysis of approximately 100 macrocyclic drugs and clinical candidates revealed that macrocycles are predominantly used for infectious disease and in oncology and that most belong to the macrolide or cyclic peptide class. A significant number (N = 34) of these macrocycles are administered orally, revealing that oral bioavailability can be obtained at molecular weights up to and above 1 kDa and polar surface areas ranging toward 250 angstrom(2). Moreover, insight from a group of "de novo designed" oral macrocycles in clinical studies and understanding of how cyclosporin A and model cyclic hexapeptides cross cell membranes may unlock wider opportunities in drug discovery. However, the number of oral macrocycles is still low and it remains to be seen if they are outliers or if macrocycles will open up novel oral druggable space.