PDF(Pubmed)
Abstract：
Nirmatrelvir (PF-07321332), a first-in-class inhibitor of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) main protease (Mpro), was developed by Pfizer under intense pressure during the pandemic to treat COVID-19. A weakness of nirmatrelvir is its limited metabolic stability, which led to the development of a combination therapy (paxlovid), involving coadministration of nirmatrelvir with the cytochrome P450 inhibitor ritonavir. However, limitations in tolerability of the ritonavir component reduce the scope of paxlovid. In response to these limitations, researchers at Pfizer have now developed the second-generation Mpro inhibitor PF-07817883 (ibuzatrelvir). Structurally related to nirmatrelvir, including with the presence of a trifluoromethyl group, albeit located differently, ibuzatrelvir manifests enhanced oral bioavailability, so it does not require coadministration with ritonavir. The development of ibuzatrelvir is an important milestone, because it is expected to enhance the treatment of COVID-19 without the drawbacks associated with ritonavir. Given the success of paxlovid in treating COVID-19, it is likely that ibuzatrelvir will be granted approval as an improved drug for treatment of COVID-19 infections, so complementing vaccination efforts and improving pandemic preparedness. The development of nirmatrelvir and ibuzatrelvir dramatically highlights the power of appropriately resourced modern medicinal chemistry to very rapidly enable the development of breakthrough medicines. Consideration of how analogous approaches can be used to develop similarly breakthrough medicines for infectious diseases such as tuberculosis and malaria is worthwhile.
摘要：
Nirmatrelvir(PF-07321332),严重急性呼吸综合征冠状病毒-2（SARS-CoV-2）主要蛋白酶（Mpro）的一流抑制剂，是由辉瑞公司在大流行期间的巨大压力下开发的，用于治疗COVID-19。Nirmatrelvir的一个弱点是其有限的代谢稳定性，这导致了联合疗法（paxlovid）的发展，涉及nirmatrelvir与细胞色素P450抑制剂利托那韦的联合给药。然而,利托那韦成分耐受性的限制减少了paxlovid的范围。为了应对这些限制，辉瑞公司的研究人员现已开发出第二代Mpro抑制剂PF-07817883(ibuzatrelvir).在结构上与Nirmatrelvir相关，包括三氟甲基的存在，虽然位置不同，ibuzatrelvir表现出增强的口服生物利用度，所以它不需要与利托那韦联合管理。伊布扎雷韦的发展是一个重要的里程碑，因为它有望增强COVID-19的治疗，而不会出现利托那韦相关的缺点。鉴于paxlovid在治疗COVID-19方面的成功，伊布扎雷韦很可能会被批准作为治疗COVID-19感染的改良药物，因此补充疫苗接种工作并改善大流行准备。nirmatrelvir和ibuzatrelvir的开发极大地突出了适当资源的现代药物化学的力量，使突破性药物的开发非常迅速。考虑如何使用类似的方法来开发用于结核病和疟疾等传染病的类似突破性药物是值得的。
