高等藥物化學(xué)課件

控制哮喘藥物

目錄ONTENTS哮喘發(fā)生機(jī)制抗炎平喘藥支氣管擴(kuò)張藥抗過敏平喘藥展望總結(jié)Developmentbackground發(fā)生機(jī)制01哮喘的危害哮喘的發(fā)生機(jī)制Drugreview抗炎平喘藥02常見的抗炎平喘藥抗炎平喘藥的平喘機(jī)制Developmentprocess支氣管擴(kuò)張藥03Bioorganic&MedicinalChemistryLetters13(2003)507–511J.Med.Chem.

1999,42,2760.WO09831661Bioorg.Med.ChemLett,

2002,12,1657–1661.IC50=7.5nMS4POCKETS1POCKETIC50=3.6nMBioorg.Med.Chem.Lett,

2004,

14,983–987.IC50=12nM223rdACSNationalMeeting,Orlando,FL,April7–11,2002,MEDI30.IC50=3.4nM2XTG:最大凝血酶產(chǎn)生時間加倍所需的抑制劑的濃度。99.8%的4與5在血漿中與血漿蛋白結(jié)合,不利于藥物對Xa因子的抗凝血活性Bioorg.Med.Chem.Lett,

2004,

14,983–987.3.973.78cLogDvalues考慮增加親水性官能團(tuán)，以減少藥物與蛋白的結(jié)合。Bioorg.Med.Chem.Lett,

2004,

14,983–987IC50=1.3nM2XTG>5μMcLogD=3.57cLogD=2.36Bioorg.Med.Chem.Lett,2004,14,989–993.Bioorg.Med.Chem.Lett,2004,14,989–993.S1S4Bioorg.Med.Chem.Lett,2021,19,2186–2189.Bioorg.Med.Chem.Lett,2021,19,2186–2189.Bioorg.Med.Chem.Lett,2021,19,2186–2189.26.1%inratsBioorg.Med.Chem.Lett,2021,19,2179–2185.B環(huán)變?yōu)?,3-噻吩環(huán)Bioorg.Med.Chem.Lett,2021,19,2179–2185.C3連著N的吡啶環(huán)C環(huán)變成2,3-噻吩環(huán)Bioorg.Med.Chem.Lett,2021,19,2179–2185.hERG(人類果蠅相關(guān)基因)編碼的鉀離子通道被抑制心室細(xì)胞復(fù)極化延遲心律失常abandonBioorg.Med.Chem.Lett,2021,19,2179–2185.42IC50=0.7nMhERGKi>10μM51IC50=2nMhERGKi>10μM11IC50=1.5nMhERGKi=1.8μM強(qiáng)烈的兩性化合物,不適于口服Bioorg.Med.Chem.Lett,2021,19,2179–2185.

Basedupontheoverallbiological,toxicologicalandPK/PDprofiles,hERGliabilityconcernandmanufacturingcost,compound11(betrixaban)waschosenastheclinicalcandidateforthisclassofanthranilamide-basedfXainhibitors.Bioorg.Med.Chem.Lett,2021,19,2179–2185.Synthesisroute工藝路線04Thelaststepisatwo-stepreaction.Andthisprocessinvolevestheuseofcorrosivechemiacalsandconditions.Soit'snotaidealroute.deficiencyOnesignificientimprovementistheuseofaone-stepprocessusingLithiumdimethylamidetoreplacethetwo-stepprocessofRoute1.improvementHowever…TwoimpuritiesSummary&Expectation總結(jié)展望05利伐沙班，拜爾阿哌沙班，施貴寶/輝瑞依度沙班，第一三共之前的工作一、達(dá)比加群，利伐沙班，阿哌沙班，依諾沙班均依賴于腎臟和肝臟代謝，這限制了其對嚴(yán)重腎損傷患者的使用。大約有20％的老年患者患有腎功能損害，因此，貝曲沙班的低腎和肝代謝是一個優(yōu)勢。二、利伐沙班、阿哌沙班和依諾沙班會和細(xì)胞色素P450相關(guān)誘導(dǎo)劑和抑制劑產(chǎn)生相互作用，影響療效，而貝曲沙班那么不會。三、貝曲沙班的半衰期顯著大于其它幾款，因此每天僅需一次給藥。四、貝曲沙班未來有可能是急性靜脈血栓栓塞的臨床標(biāo)準(zhǔn)用藥，因為它比依諾肝素注射更方便，并且可以在出院后長時間〔35至42天〕內(nèi)使用。貝曲沙班的優(yōu)勢An