老药结构立新功！药明康德如何用这项技术为新型分子“撞开”一扇新门？| Bilingual

从20世纪40年代可的松（cortisone）在类风湿性关节炎治疗中惊艳亮相，到口服避孕药的诞生改变无数人的生活——被《经济学人》（The Economist）杂志评为20世纪科学与技术伟大的进步之一，再到如今广泛应用于抗肿瘤、免疫调节及代谢疾病等领域，甾体化合物在现代药物研发中始终占据着不可替代的地位。

然而，随着新药靶点发现难度的增加、甾体分子结构日趋复杂，其研发与生产面临多重挑战。一方面，商业化可及的甾体药物中间体多集中于经典母核，新型结构适配的定制化中间体供给不足，提高了合成路线设计与工艺放大的门槛；另一方面，甾体骨架含多个连续手性中心，部分位点的反应选择性难以精准调控，不仅增加早期纯化成本，也易在规模放大过程中引发更多副反应，延长杂质研究周期。

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深耕甾体化学：系统性构筑经验证的平台能力

面对甾体化学的研发挑战，药明康德研发化学服务部（Research Chemistry Services，RCS）在十多年前便开始布局甾体化学能力，在攻克关键难题的过程中积累了丰富经验。依托长期的能力与经验沉淀，RCS近年来进一步构建了覆盖药物发现、分子优化到工艺开发与规模化生产的甾体化学综合技术平台。如今，平台累计合成超过1万种甾体类化合物。

在复杂多手性中心构建与结构精准修饰方面，平台建立了20余种甾体手性中心构建方法，并配套丰富的甾体高级中间体与定制化路线设计能力，可高效支持从苗头化合物到先导化合物的优化、新结构开发到聚焦化合物库构建等早期研究需求。

针对甾体分子的结构特点，RCS能够通过路线开发、杂质与代谢物合成、同位素标记及绝对构型解析等能力，实现对候选分子的系统性研究与优化。同时，平台支持毫克级至公斤级的化合物合成与交付，并通过早期工艺开发与放大研究，有效缩短开发周期。平台的能力已经在诸多项目中得到验证。

曾有客户因棘手的工艺开发难题找到药明康德RCS团队：其目标甾体分子的原始合成路线步骤冗长，且存在区域选择性差、工艺放大难等问题。面对困局，RCS团队依托甾体合成经验与技术能力，重新审视并成功开发出一条全新路线——总路线从7步缩短至3步，总收率也提升了两倍以上。

此次超预期的交付赢得了客户认可，也为双方建立了坚实的信任基础。随后，该客户在新业务开展时毫不犹豫地再次选择与RCS开展项目合作，共同推进更具挑战性的甾体分子项目。

在另一个案例中，依托公司甾体化学综合技术平台及某关键中间体的成功应用，RCS团队仅用23天便完成客户目标甾体化合物的合成，相较行业常规约2个月的周期，时间大幅缩短。

这些实践，既是药明康德甾体化学综合技术平台赋能能力的具体体现，也印证了平台能力与行业需求的深度契合。

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持续精进：赋能新分子研发

甾体药物的价值远不止于传统治疗领域，凭借独特的刚性多环骨架结构与生物学特性，甾体结构正成为突破新型分子成药瓶颈的关键功能单元。

近年来，靶向蛋白降解剂、抗体偶联药物（ADCs）、寡核苷酸等新分子类型不断拓展可干预靶点的范围。在部分新分子设计中，甾体片段可作为关键结构单元，用于调节稳定性、靶向特异性或递送性能。这对甾体化学的高选择性衍生化改造能力提出了更高要求。

为响应这类前沿新分子的研发需求，药明康德RCS甾体化学综合技术平台持续迭代其技术能力。目前，平台能够对ADCs和蛋白降解嵌合体等新型分子中的甾体片段进行高效且高选择性的衍生化改造。以某款基于甾体骨架的ADC载荷工艺开发项目为例，平台不仅快速完成了百毫克级合成验证，更通过路线优化大幅提升了总收率，充分验证了平台支持含甾体结构的新分子从早期设计到可放大合成的能力。

目前，药明康德RCS已将甾体化学与新分子类型开发深度结合，可支持包含甾体骨架的抗体偶联药物、靶向蛋白降解剂、前药及氮芥类分子设计与合成，并与分析服务、反应条件筛选、重结晶平台、流动化学、光氧化还原及电化学等技术协同运行，实现从分子创新到可放大生产的无缝衔接。通过整合长期经验、模块化技术能力与跨平台协同，甾体化学平台能够为客户提供稳定、高效且可扩展的化学赋能，助力复杂甾体分子及新型偶联分子的研发与转化。

甾体化学综合技术平台的演进，是药明康德一体化、端到端的CRDMO能力不断精进的缩影——通过在甾体化学领域的持续积累与迭代，助力合作伙伴提升研发效率、缩短项目周期，并提供从分子设计和优化到工艺开发与规模化生产的全流程解决方案。（如需了解药明康德研发化学服务或业务咨询，请点击文末“阅读原文”）

未来，随着更多复杂甾体分子及新型分子模式的涌现，药明康德将持续通过一体化、端到端的CRDMO赋能平台，助力全球合作伙伴推动创新疗法更快惠及患者。

How WuXi AppTec Addresses the Challenges of Steroid Drug Discovery and Development

Steroid compounds hold an important position in modern drug discovery and development, from the introduction of cortisone in the 1940s for rheumatoid arthritis, to the advent of the oral contraceptive pill, which transformed reproductive health and the lives of millions of people. Today, steroids remain widely used in the treatment of cancer, immune disorders, and metabolic diseases.

However, the development and manufacturing of steroid compounds present distinct challenges as molecular structures become increasingly complex. First, commercially available steroid intermediates are largely limited to conventional core scaffolds, while customized intermediates suitable for novel structures remain scarce, complicating synthetic route design and process scale-up. Second, steroid scaffolds often contain multiple contiguous stereocenters, making it difficult to achieve precise regioselectivity and stereoselectivity at specific positions. These challenges can increase purification requirements during early development, promote side reactions during scale-up, and extend the time needed for impurity identification and control. 

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Developing Proven Capabilities in Steroid Chemistry 

More than a decade ago, WuXi AppTec's Research Chemistry Services (RCS) began developing specialized capabilities in steroid chemistry to address the synthetic and process challenges associated with structurally complex steroid molecules. Building on this experience, RCS has established a comprehensive steroid chemistry platform covering discovery, optimization, process development, and large-scale production. Today, the platform has synthesized over 10,000 steroid molecules. 

To enable the construction and modification of complex steroid scaffolds, RCS has established over 20 methods for controlling stereochemistry at specific positions. These capabilities are complemented by customized route design and access to a diverse range of advanced steroid intermediates, supporting activities such as hit-to-lead optimization, novel scaffold development, and focused library generation. RCS also provides capabilities in synthetic route development, impurity and metabolite synthesis, isotope labeling, and absolute-configuration determination. Together, these capabilities enable the systematic characterization and optimization of steroid candidates based on their structural and physicochemical properties. The platform supports compound synthesis and delivery at scales ranging from milligrams to kilograms, as well as early process development and scale-up, helping clients advance programs efficiently through successive stages of development.

In one project, a client sought support for a steroid molecule whose original synthetic route involved numerous steps, poor regioselectivity, and limited reproducibility during scale-up. RCS redesigned the route, reducing the total number of steps from 7 to 3 and more than doubling the overall yield. The team exceeded expectations and earned positive feedback from the client. Following completion of the project, the client engaged RCS for an additional and more technically challenging steroid synthesis program.

In another project, RCS combined its steroid chemistry platform with the use of a key steroid intermediate to complete the synthesis of a target compound in 23 days. Given that the industry-standard timeline is approximately two months, the synthesis timeline was significantly shortened.

These examples demonstrate how WuXi AppTec’s comprehensive steroid chemistry platform supports steroid drug development and how its integrated development capabilities align with industry needs.

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Extending Steroid Chemistry Capabilities to Emerging Therapeutic Modalities 

The value of steroid chemistry extends beyond the development of conventional steroid-based therapeutics. With their rigid polycyclic structures and distinctive physicochemical and biological properties, steroid scaffolds can serve as functional components in the design of emerging therapeutic modalities, helping researchers modulate molecular properties that may otherwise limit drug development.

New modalities, including targeted protein degraders, antibody-drug conjugates (ADCs), and oligonucleotide therapeutics, are expanding the range of addressable targets and therapeutic design strategies. In some of these molecules, steroid-derived fragments can be incorporated as structural or functional components to modulate stability, targeting, or delivery. The development of such molecules requires steroid chemistry capabilities that enable precise, highly selective derivatization at specific positions on structurally complex steroid scaffolds.

RCS's comprehensive steroid chemistry platform has evolved in response to the growing demands of these new modalities. It now supports the efficient and highly selective derivatization of steroid fragments used in ADCs and targeted protein degraders. In one case involving the development of an ADC payload based on a steroid scaffold, the platform delivered hundred‑milligram-scale compounds for validation and improved the overall yield through route optimization, demonstrating its ability to support steroid-containing new modalities from early design through scalable synthesis.

WuXi AppTec’s RCS integrates steroid chemistry with the development of innovative therapeutic modalities, supporting the design and synthesis of ADCs, targeted protein degraders, prodrugs, and nitrogen mustard derivatives that incorporate steroid-derived structural or functional components. The platform also draws on complementary capabilities in analytical services, reaction-condition screening, recrystallization, flow chemistry, photoredox chemistry, and electrochemistry to support progression from molecular design to scalable synthesis. By integrating long-term experience, modular technical capabilities, and cross-platform synergy, the steroid chemistry platform provides clients with stable, efficient, and scalable synthetic solutions, accelerating the R&D of complex steroids and novel conjugate molecules.

The continued development of RCS’s steroid chemistry capabilities reflects the broader evolution of WuXi AppTec’s integrated, end-to-end CRDMO model. Through ongoing technical refinement and cross-functional collaboration, RCS helps clients improve discovery and development efficiency, shorten project timelines, and obtain one-stop solutions covering molecular design, process development, and scale-up.

As increasingly complex steroid molecules and emerging therapeutic modalities create new development demands, WuXi AppTec will continue to leverage its integrated CRDMO platform to help clients advance innovative therapies for patients worldwide. 

Key Takeaways:

1. WuXi AppTec’s Research Chemistry Services (RCS) has built an integrated steroid chemistry platform covering early discovery, molecular optimization, process development, and large-scale manufacturing.

2. With more than a decade of experience and over 10,000 steroid compounds synthesized, RCS has developed extensive expertise in addressing the stereochemical and synthetic challenges associated with complex steroid molecules.

3. Capabilities in route development, impurity and metabolite synthesis, isotope labeling, and absolute-configuration determination support the systematic characterization and optimization of steroid candidates.

4. RCS combines specialized steroid chemistry expertise with modular technical capabilities and cross-platform collaboration to support the design, synthesis, optimization, and scale-up of complex steroid compounds and novel conjugates.

5. The platform applies steroid chemistry to emerging therapeutic modalities, supporting ADCs, targeted protein degraders, prodrugs, and nitrogen mustard derivatives that incorporate steroid-derived components, while drawing on complementary capabilities in analytical services, reaction-condition screening, recrystallization, flow chemistry, photoredox chemistry, and electrochemistry.

For more information about WuXi AppTec’s Research Chemistry Services or business collaboration inquiries, please click “Read More” at the end of this article.

参考资料：

[1] FDA's Approval of the First Oral Contraceptive, Enovid. Retrieved June 10, 2026, from

[2] Project W – The Power of the Pill. Retrieved June 10, from

[3] Zhu, Jiacheng, Guoshun Luo and Hua Xiang. “Approved Steroidal Drugs (2000-2025): A Medicinal Chemistry Perspective.” Journal of medicinal chemistry (2026): n. pag.

[4] 从避孕药到抗癌、抗抑郁：这个经典分子骨架，为何还能不断诞生新药？Retrieved June 10, 2026, from

[5] PENG H D, WANG Y Y, JIANG K, et al. A dual role reductase from phytosterols catabolism enables the efficient production of valuable steroid precursors. Angewandte Chemie International Edition, 2021, 60(10): 5414-5420.

[6] DONOVA M V, EGOROVA O V. Microbial steroid transformations: current state and prospects[J]. Applied Microbiology and Biotechnology, 2012, 94(6): 1423-1447.

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