Entospletinib Dimesylate

1背景当前药物化学项目集中于更多更具挑战性的生物靶点，候选药物的分子复杂性大大增加。为此，药物研究者们不断寻找创新的功能分子基团以应对这一挑战。今天我们要分享的是伦敦帝国理工学院化学系分子科学研究中心发表在Journal of Medicinal Chemistry上的文章：Oxetanes in Drug Discovery Campaigns。文章介绍了氧杂环丁烷在药物发现中的应用以及应用中的一些优缺点。四元杂环因其具有低分子量，高极性和特异的三维属性而深受研究者们的欢迎，其中氧杂环丁烷基团被报道的更多（图1）。 图1. (a) 具有生物活性的四元杂环的例子；（b）文献中报道四元杂环的数量变化氧杂环丁烷基团在天然产物中常有出现，最著名的有FDA批准的紫杉醇（图2a），虽然氧杂环丁烷被证明不是紫杉醇生物活性的必要结构，但含氧杂环丁烷基团的类似物的亲和力和细胞毒性低于紫杉醇的母体结构。 图2. (a) 紫杉醇；(b) gem-二甲基和羰基衍生物的等排体 3,3-二取代的氧杂环丁烷可以作为gem-二甲基和羰基的等排体（图2b），Carreira 团队和罗氏公司合作证明氧杂环丁烷可以作为gem-二甲基的等排体来阻断候选药物中C-H活性位点的代谢 [1]；氧杂环丁烷还可以作为羰基的等排体用来改善药物分子的代谢稳定性及提高药物分子的水溶性等性质。2应用举例氧杂环丁烷在专利和学术期刊中广泛出现，目前有七种包含氧杂环丁烷的候选药物正在进行临床试验（图3a-3g）。七种候选药物中有超过50%的结构是氨基-氧杂环丁烷，其中氧杂环丁烷基团可以减弱氨基的碱度。此外，七种化合物中有6种化合物的氧杂环丁烷是3位取代，因为3位取代的稳定性和可合成性更高。通常在药物设计的后期引入氧杂环丁烷来改善先导化合物的PK性质（logD、溶解度、清除率或碱度等）。 图3a. Crenolanib[2] 图3b. Fenebrutinib[3]图3b Fenebrutinib中氧杂环丁烷的引入降低了化合物4的pKaH，对化合物的溶解度和药代动力学特性也有一定的益处。 图3c. Ziresovir[4]图3c 中Ziresovir，在研发后期通过引入氧杂环丁烷来降低化合物5中氨基的碱度，氧杂环丁烷小体积的特性也有助于降低分布体积，避免药物在组织中堆积，降低了毒性风险。 图3d. Lanraplenib[5]图3d 中Entospletinib 由于其不充分的溶解度，与质子泵抑制剂不良的相互作用以及吗啉环氧化导致的高代谢清除率退出了临床开发。在后期优化阶段引入4-乙基哌嗪替换吗啉改善了化合物的代谢稳定性，随后引入氧杂环丁烷替代乙基，降低了化合物的碱度，提高了在 pH 2 和 Caco-2 渗透性下的溶解度。 图3e. Danuglipron[6]图3e Danuglipron 中氧杂环丁烷作为一个小的极性头被引入，它增加了化合物的活性，没有对 LogD 和其他物理化学性质（如清除率和毒性）产生负面影响。 图3f. GDC-0349[7]图3f 化合物7有较差的游离血浆清除率和避免由细胞色素P450酶类（CYP酶）时间依赖性抑制（TDl），这可能导致药物存在潜在的毒性问题。将嘧啶环换成烷基确实将CYP抑制降低了10倍以上，但心脏毒性增高（hERG：IC50= 8.5 μM），这与叔烷基胺碱度增加有关（pKaH= 7.6）。GDC-0349 在氮上引入氧杂环丁烷取代基降低了pKaH，同时降低了hERG毒性，与化合物7相比，游离血浆清除率也降低了10倍。 图3g. PF-06821497[8]图3g中先导化合物8是一种有效的EZH2抑制剂，但代谢稳定性差且溶解度不足。可通过降低LogD和增加立体性来改善这两种特性。最后化合物9引入了甲氧基和氧杂环丁烷，显著改善了代谢和溶解度特性，并使化合物更适合蛋白口袋。 图4. 化合物PF-06821497与EZH2的共晶体结构新引入的氧杂环丁烷立体中心对结合很重要，化合物PF-06821497与 EZH2 复合物的共晶结构表明（图4），氧杂环丁烷取代基在蛋白空腔中占据了一个确定的空间，氧杂环丁烷中的CH 基团和两个酪氨酸侧链之间存在两个潜在的 CH−π相互作用。3小结氧杂环丁烷基团在药物发现中有非常重要的应用，研究表明，氧杂环丁烷的稳定性与其取代模式密切相关，其中3,3-二取代最稳定。研究者们揭示了氧杂环丁烷在药物研发中的许多潜在优势，但也发现了很多的挑战。氧杂环丁烷的潜在优势1.氧杂环丁烷的诱导吸电子效应可以降低相邻基团的pKaH （α位降低约2.7、β位降低约1.9、γ位降低约0.7、δ位降低约0.3），可通过引入氧杂环丁烷来减少或消除药物化合物的碱性。2.氧杂环丁烷中sp3杂化的碳原子增加了化合物的立体性，这种构象效应可以增加化合物的水溶性。3.氧杂环丁烷的体积小，极性大，可用于阻断代谢不稳定的位点，并且不会显著增加化合物的分子量和亲脂性。4.氧杂环丁烷可以作为羰基官能团的生物等排体，这可能有助于规避羰基特异性酶降解，提高水溶性，获得新的IP空间。5.氧杂环丁烷适度的环应变可以引导通过活性药物成分（APIs）代谢而被微粒体环氧化物水解酶（mEH）降解，从而避免由CYP酶清除导致的肝毒性。氧杂环丁烷的潜在劣势，面临的挑战及未来的方向1.氧杂环丁烷的合成仍然具有挑战性。2.氧杂环丁烷构建模块的选择是有限的，这种约束影响了药物化合物中氧杂环丁烷结构的取代模式。3.氧杂环丁烷在酸性条件或高温条件下是不稳定的，所以预测给定的氧杂环丁烷取代模式的稳定性是具有挑战性的。4.氧杂环丁烷在严苛条件下的潜在不稳定性可能成为多步大规模合成的问题，所以通常氧杂环丁烷仅在药物开发的最后阶段引入，以补救一些有问题的物理化学性质，如溶解度或代谢稳定性。5.氧杂环丁烷化合物相关性质的数据集有限，限制了基于数据的预测。参考文献（上下滑动可查看更多）本文：Rojas, J. Oxetanes in Drug Discovery Campaigns. J. Med. Chem. 2023, 66, 12697–12709.[1]. Wuitschik, G.; etal. Oxetanes as Promising Modules in Drug Discovery. Angew. Chem., Int. Ed. 2006, 45, 7736−7739.[2]. Smith, C. C.; etal. Crenolanib Is a Selective Type I Pan-FLT3 Inhibitor. Proc. Natl. Acad. Sci. U. S. A. 2014, 111, 5319−5324.[3]. Crawford, J. J.; Zhang, H. In ACS Symposium Series; American Chemical Society, 2019; Vol. 1332, pp 239−266.[4]. Zheng, X.; etal. Discovery of Benzoazepinequinoline (BAQ) Derivatives as Novel, Potent, Orally Bioavailable Respiratory Syncytial Virus Fusion Inhibitors. J. Med. Chem. 2018, 61, 10228−10241.[5]. Blomgren, P.; etal. Discovery of Lanraplenib (GS-9876): A Once-Daily Spleen Tyrosine Kinase Inhibitor for Autoimmune Diseases. ACS Med. Chem. Lett. 2020, 11, 506−513.[6]. Griffith, D. A.; etal. A Small-Molecule Oral Agonist of the Human Glucagon-like Peptide-1 Receptor. J. Med. Chem. 2022, 65, 8208−8226.[7]. Pei, Z.; etal. Discovery and Biological Profiling of Potent and Selective mTOR Inhibitor GDC-0349. ACS Med. Chem. Lett. 2013, 4, 103−107.[8]. Kung, P.-P.; etal. Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(Methoxy(Oxetan-3-yl)Methyl)-2-((4- Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihy-droisoquinolin-1(2H)-one (PF-06821497). J. Med. Chem. 2018, 61, 650−665.声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号   粉丝群/投稿/授权/广告等请联系公众号助手 觉得本文好看，请点这里↓

Replacing the three jettisoned C-suite roles will be four SPV positions overseeing: R&D; clinical development; corporate strategy and portfolio management; and corporate operations and legal. Kronos Bio had already trimmed back its headcount and pipeline in the wake of a mid-stage cancer flop. Now, it’s the company’s C-suite who are heading to the exits. The biotech has “eliminated three executive officer roles”—meaning Chief Medical Officer Jorge DiMartino, M.D., Chief Scientific Officer Christopher Dinsmore, Ph.D., and Chief Operating Officer and General Counsel Barbara Kosacz will all be out of a job. The company explained the changes were needed to ensure a “streamlined leadership structure designed to focus on pipeline advancement and align with Kronos Bio’s current operating needs.” The three executives will leave the company on Feb.16, although they will remain as strategic advisors for the business, according to a Jan. 25 press release. The leadership shakeup follows a headcount reduction of 19% in November in order to fund KB-0742, a CDK9 inhibitor currently in a phase 1/2 trial for solid tumors and non-Hodgkin lymphoma. A month after the layoffs, Kronos said it was discontinuing a cancer trial for lanraplenib and seeking a partner for the SYK inhibitor in the wake of a mid-stage trial flop. “This new leadership structure is designed to streamline our operations and reflects our ongoing effort to advance our pipeline, optimize our resources, and efficiently deliver on our business objectives,” CEO Norbert Bischofberger, Ph.D., said in the release. “I would like to thank Jorge, Chris, and Barbara for their leadership and dedication, and I wish them well in their future endeavors,” Bischofberger added. “They each built and managed strong teams, laying the groundwork for this new structure and preparing our future leaders for success.” Replacing the three jettisoned C-suite roles will be four SPV positions overseeing R&D; clinical development; corporate strategy and portfolio management; and corporate operations and legal. Those positions are filled by Charles Lin, Ph.D., Elizabeth Olek, Rocio Martin Hoyos and Allison Frisbee, respectively. Kronos said it expects to make savings from the changes, even after termination costs are accounted for. Besides KB-0742, Kronos has a partnership with Roche’s Genentech for several undisclosed discovery programs. Inked a year ago, the Genentech partnership is crucial for Kronos, coming right after the biotech kicked a late-stage AML asset called entospletinib to the curb. The Roche unit jumped in to save the day for the struggling biotech with a $20 million upfront payment plus milestones that could top $177 million for the first program and $100 million for the first licensed product. Kronos also recently revealed a new development candidate, dubbed KB-9558. The preclinical asset is designed to modulate the IRF4 transcription regulatory network—a key driver in multiple myeloma.