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Discovery of 6-(4-{[5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic Acid: A Novel FXR Agonist for the Treatment of Dyslipidemia
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2015-12-02 00:00:00 , DOI: 10.1021/acs.jmedchem.5b01161 Michael J. Genin , Ana B. Bueno , Javier Agejas Francisco , Peter R. Manninen , Wayne P. Bocchinfuso , Chahrzad Montrose-Rafizadeh , Ellen A. Cannady , Timothy M. Jones , John R. Stille 1 , Eyas Raddad 1 , Charles Reidy , Amy Cox , M. Dodson Michael , Laura F. Michael
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2015-12-02 00:00:00 , DOI: 10.1021/acs.jmedchem.5b01161 Michael J. Genin , Ana B. Bueno , Javier Agejas Francisco , Peter R. Manninen , Wayne P. Bocchinfuso , Chahrzad Montrose-Rafizadeh , Ellen A. Cannady , Timothy M. Jones , John R. Stille 1 , Eyas Raddad 1 , Charles Reidy , Amy Cox , M. Dodson Michael , Laura F. Michael
Affiliation
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The farnesoid X receptor (FXR) is a member of the “metabolic” subfamily of nuclear receptors. Several FXR agonists have been reported in the literature to have profound effects on plasma lipids in animal models. To discover novel and effective therapies for dyslipidemia and atherosclerosis, we have developed a series of potent FXR agonists that robustly lower plasma LDL and vLDL in LDLr–/– mice. To this end the novel piperidinylisoxazole system LY2562175 was discovered. This molecule is a potent and selective FXR agonist in vitro and has robust lipid modulating properties, lowering LDL and triglycerides while raising HDL in preclinical species. The preclinical ADME properties of LY2562175 were consistent with enabling once daily dosing in humans, and it was ultimately advanced to the clinic for evaluation in humans. The synthesis and biological profile of this molecule is discussed.
中文翻译：
6-（4-{[5-环丙基-3-（2,6-二氯苯基）异恶唑-4-基]甲氧基}哌啶-1-基）-1-甲基-1 H-吲哚-3-羧酸的发现：新型FXR激动剂，用于血脂异常的治疗
法尼醇X受体（FXR）是核受体“代谢”亚家族的成员。在文献中已经报道了几种FXR激动剂对动物模型中的血浆脂质具有深远的影响。为了发现针对血脂异常和动脉粥样硬化的新颖有效的疗法，我们开发了一系列有效的FXR激动剂，可有效降低LDLr – / –小鼠的血浆LDL和vLDL。为此，发现了新的哌啶基异恶唑系统LY2562175。该分子是体外有效的选择性FXR激动剂，具有强大的脂质调节特性，可降低临床前物种中的LDL和甘油三酸酯，同时提高HDL。LY2562175的临床前ADME特性与在人中每天给药一次相一致，并且最终被推广到临床中以在人中进行评估。
更新日期：2015-12-02
中文翻译：
6-（4-{[5-环丙基-3-（2,6-二氯苯基）异恶唑-4-基]甲氧基}哌啶-1-基）-1-甲基-1 H-吲哚-3-羧酸的发现：新型FXR激动剂，用于血脂异常的治疗
法尼醇X受体（FXR）是核受体“代谢”亚家族的成员。在文献中已经报道了几种FXR激动剂对动物模型中的血浆脂质具有深远的影响。为了发现针对血脂异常和动脉粥样硬化的新颖有效的疗法，我们开发了一系列有效的FXR激动剂，可有效降低LDLr – / –小鼠的血浆LDL和vLDL。为此，发现了新的哌啶基异恶唑系统LY2562175。该分子是体外有效的选择性FXR激动剂，具有强大的脂质调节特性，可降低临床前物种中的LDL和甘油三酸酯，同时提高HDL。LY2562175的临床前ADME特性与在人中每天给药一次相一致，并且最终被推广到临床中以在人中进行评估。
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