高等药物化学

控制哮喘药物,目 录,ONTENTS,哮喘发生机制,抗炎平喘药,支气管扩张药,抗过敏平喘药,展 望总 结,哮喘的危害,哮喘的发生机制,常见的抗炎平喘药,抗炎平喘药的平喘机制,Bioorganic & Medicinal Chemistry Letters 13 (2003) 507511,J. Med. Chem. 1999, 42, 2760.,WO 09831661,Bioorg. Med. Chem Lett, 2002, 12, 16571661.,IC50=7.5 nM,S4 POCKET,S1 POCKET,IC50=3.6 nM,Bioorg. Med. Chem. Lett, 2004, 14, 983987.,IC50=12 nM,223rd ACS National Meeting, Orlando, FL, April 711, 2002, MEDI 30.,IC50=3.4 nM,2XTG:最大凝血酶产生时间加倍所需的抑制剂的浓度。,99.8%的4与5在血浆中与血浆蛋白结合,不利于药物对Xa因子的抗凝血活性,Bioorg. Med. Chem. Lett, 2004, 14, 983987.,3.97,3.78,cLogD values,考虑增加亲水性官能团，以减少药物与蛋白的结合。,Bioorg. Med. Chem. Lett, 2004, 14, 983987,IC50=1.3nM2XTG5McLogD=3.57,cLogD=2.36,Bioorg. Med. Chem. Lett, 2004,14, 989993.,Bioorg. Med. Chem. Lett, 2004,14, 989993.,S1,S4,Bioorg. Med. Chem. Lett, 2009,19, 21862189.,Bioorg. Med. Chem. Lett, 2009,19, 21862189.,Bioorg. Med. Chem. Lett, 2009,19, 21862189.,26.1% in rats,Bioorg. Med. Chem. Lett, 2009,19, 21792185.,B环变为2,3-噻吩环,Bioorg. Med. Chem. Lett, 2009,19, 21792185.,C3连着N的吡啶环C环变成2,3-噻吩环,Bioorg. Med. Chem. Lett, 2009,19, 21792185.,hERG(人类果蝇相关基因)编码的钾离子通道被抑制,心室细胞复极化延迟,心律失常,abandon,Bioorg. Med. Chem. Lett, 2009,19, 21792185.,42IC50=0.7 nMhERG Ki 10 M,51IC50=2 nMhERG Ki 10 M,11IC50=1.5nMhERG Ki =1.8 M,强烈的两性化合物,不适于口服,Bioorg. Med. Chem. Lett, 2009,19, 21792185.,Based upon the overall biological, toxicological and PK/PD profiles, hERG liability concern and manufacturing cost, compound 11 (betrixaban) was chosen as the clinical candidate for this class of anthranilamide-based fXa inhibitors.,Bioorg. Med. Chem. Lett, 2009,19, 21792185.,The last step is a two-step reaction. And this process involeves the use of corrosive chemiacals and conditions. So its not a ideal route.,deficiency,One significient improvement is the use of a one-step process using Lithium dimethylamide to replace the two-step process of Route 1.,improvement,However,Two impurities,利伐沙班，拜尔,阿哌沙班，施贵宝/辉瑞,依度沙班，第一三共,之前的工作,一、达比加群，利伐沙班，阿哌沙班，依诺沙班均依赖于肾脏和肝脏代谢，这限制了其对严重肾损伤患者的使用。 大约有20的老年患者患有肾功能损害，因此，贝曲沙班的低肾和肝代谢是一个优势。二、利伐沙班、阿哌沙班和依诺沙班会和细胞色素P450相关诱导剂和抑制剂产生相互作用，影响疗效，而贝曲沙班则不会。 三、贝曲沙班的半衰期显著大于其它几款，因此每天仅需一次给药。四、贝曲沙班未来有可能是急性静脉血栓栓塞的临床标准用药，因为它比依诺肝素注射更方便，并且可以在出院后长时间（35至42天）内使用。,贝曲沙班的优势,Andexanet alfa,