BMS-986020

肺纤维化是一种长期的，可能危及生命的肺部间质疾病（ILD），截至2021年，全球有超过70万的成年患者。现今对于肺纤维化和间质性肺纤维化的治疗还未有有效且让人满意的疗法。BMS-986278作为全球首个溶血磷脂酸受体1LPA1抑制剂，目前正在开展治疗肺纤维化和间质性肺纤维化的三期临床，有望成为“first in class”，为肺纤维化和间质性肺纤维化患者提供新的医疗选择。BMS-986278的研发历程与大部分新药研发过程一样，充满了艰辛，2021年BMS的科学家们发表的文章《Discovery of an Oxycyclohexyl Acid Lysophosphatidic Acid Receptor 1(LPA1)Antagonist BMS-986278 for the Treatment of Pulmonary Fibrotic Diseases》披露了BMS-986278研发最精彩的部分，通过临床中失败的分子BMS-986020进行结构优化，最终成功获得理想化合物BMS-986278。下面我将采用AiDMET成药性预测平台对这一优化阶段进行评估和解释，从中可以看到AiDMET的预测结果与真实临床结果非常接近，这也提示我们，如果在早期设计中采用AiDMET预测平台对化合物进行最优化的设计，可以提高临床成功率并节约上市时间。表1 全球进入临床的LPA1抑制剂注：BMS在临床2期暂停研究的BMS-986020分子结构的基础上进行改进，获得BMS-986278数据来源：药智数据图1 BMS-986020和BMS-986278（Admilparant）化学结构2011年，Bristol-Myers Squibb通过收购Amira Pharmaceuticals，将一款首创的抗纤维化药物BMS-986020（AM-152）纳入研发管线，但在后续的一项6个月的IPF患者Ⅱ期临床试验中，BMS-986020虽然证明了其有希望的疗效机制，但是由于严重胆汁淤积症的发生，BMS主动终止了其临床计划。1.BMS-986020存在的问题BMS后续对BMS-986020进行回顾性的非临床毒理学研究，表明BMS-986020的肝胆毒性很可能是由于结构和（或）化学类型所导致的脱靶效应，而不是LPA1的靶点本身引起的。化合物BMS-986020存在的问题：（1）BMS-986020的N-氨基甲酸酯在人体内容易裂解，生成没有活性代谢产物1a（Mlo_1），因此需要较大的起效给药剂量，导致后期临床中存在安全性隐患。图2 AiDMET预测的BMS-986020的代谢产物和文献中给出的主要代谢产物一致（2）肝脏毒性，关于BMS-98602的临床肝胆毒性的原因，最合理的机制假说是肝脏胆汁酸水平的增加。这种毒性通常归因于BSEP（胆盐输出泵）等关键转运体破坏正常的胆汁酸稳态，以及导致胆汁磷脂水平的降低。BMS-986020抑制一些重要的胆汁酸转运体（BSEP、MPR3和OATP1B1），这些转运体被证明会介导肝胆毒性。图3 AiDMET预测出BMS-986020的肝毒性和转运体抑制，肝毒性以及对BSEP的抑制，是BMS-986020产生严重副作用的主要原因2.结构优化方向基于BMS-986020存在问题的问题BMS提出了化合物结构的改进方法，（1）先降低亲脂性（cLogP）和（2）增加C(sp3)分数（定义为分子中C(sp3)碳/总碳的数量）[即分子中较少的芳香碳，这是降低毒性风险的一种方法]，（3）降低对关键肝转运蛋白（如BSEP、MPR3和OATP1B1）抑制作用，（4）用一个代谢上药效更强的基团取代不稳定异恶唑N-氨基甲酸酯部分。3.结构优化过程BMS-986020（化合物1）是一种亲脂性羧酸，具有相对较高的cLogP值5.87（在pH 6.5条件下，摇瓶测得的logD=3.60）、少量的可旋转键和0.21的低C(sp3)分数。这些性质的组合可能会导致药剂学不理想，经过初步的SAR发现，化合物4反式(±)-3-氧苯基环己基酸具有更高的C(sp3)值0.35和略低的cLogP值4.84，因此化合物4为系统地探索分子中的其他药效团提供了一个很好的起点。图4 文献中给出的化合物1、3、4的理化活性数据以及AiDMET预测的理化性质数据由于N-氨基甲酸异恶唑部分在人体内代谢不稳定，因此对化合物4的N-氨基甲酸酯部分的SAR进行了广泛的研究。研究者主要从下图的三个方向进行SAR研究，最终发现了N-环丁基甲基N-甲基氨基甲酸酯类似物25（BMS-986234），这是在该项目这一阶段的第一个临床候选物。化合物25的C(sp3)分数（0.625）和极性（cLogP=3.16；logD（pH6.5）=2.30）均显著高于BMS-986020（化合物1）。化合物25具有良好抑制效力和成药性质。图5 以化合物4为起点的三种SAR研究图6 AiDMET预测化合物1和化合物25的性质，化合物25与初始化合物1（BMS-986020）相比，极性显著升高（logD降低）溶解度增大，血浆蛋白结合率降低（游离部分升高），肝毒性降低，BSEP的抑制降低。BMS对化合物25的进一步SAR研究，想进一步改善代谢以及清除率，研究集中在25的N-氨基甲酸酯部分和两个杂芳环的变化上，最终获得极性较高且活性、转运体和PK特性均较好的化合物33，作为目前的LPA1拮抗剂临床候选药物BMS-986278进入开发阶段。图7 化合物25和化合物33（Admilparan）的结构在BMS-986020的成药性优化过程中，AiDMET平台预测出的结果与真实试验结果高度吻合，包括有代谢产物的预测、转运蛋白抑制的评估以及结构优化后的成药性提升预测，这充分证明了该平台的强大的预测能力和精准度。天智药成团队开发的AiDMET成药性预测平台是一款功能强大的分子成药性预测工具，利用人工智能预测模型从分子结构出发全面呈现出一种新化学物质的潜在ADMET成药性参数：从简单的物理化学性质（如氢键能力、分子质量、溶解度和亲脂性等）到完整的ADMET参数预测（例如吸收百分比、生物利用度、清除率、分布体积和半衰期等），能够为新药小分子提供吸收、分布、代谢、排泄、毒性等160多项参数的预测服务，让您的新药设计更高效。AiDMET成药性预测平台已经上线，我们诚邀您体验这一新平台，如有兴趣请联系我们。参考文献：1.Cheng,PTW.;Kaltenbach,RF.;et al.;Discovery of an Oxycyclohexyl Acid Lysophosphatidic Acid Receptor 1(LPA1)Antagonist BMS-986278 for the Treatment of Pulmonary Fibrotic Diseases.J Med Chem.2021 Nov 11;64(21):15549-15581.2.Gill,MW.;Murphy BJ.;et al.;Mechanism of hepatobiliary toxicity of the LPA1 antagonist BMS-986020 developed to treat idiopathic pulmonary fibrosis:Contrasts with BMS-986234 and BMS-986278.Toxicol Appl Pharmacol.2022 Mar 1:438:115885.3.Sivaraman,L.;GillStructure,M.;Structure dependence and species sensitivity of in vivo hepatobiliary toxicity with lysophosphatidic acid receptor 1(LPA1)antagonists.Toxicol Appl Pharmacol.2022 Mar 1:438:115846.声明：本内容仅用作医药行业信息传播，为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。责任编辑 | 罗燕 阅读原文，是受欢迎的文章哦

In September last year, the South Korean biopharmaceutical company GPCR Therapeutics published a research paper in "Cell Communication and Signaling" about the direct interaction between two different GPCRs (CXCR4 and LPA1). Through various in vitro experiments, the company discovered that the efficacy of LPA1 inhibitors could be enhanced to its maximum potential by inhibiting CXCR4, thereby providing scientific evidence that the combination of CXCR4-LPA1 inhibitors might be a necessary condition for comprehensive antifibrotic activity. Based on this discovery, GPCR Therapeutics filed a provisional patent application for a combined therapeutic method involving CXCR4-LPA1 inhibitors. GPCR Therapeutics will collaborate with Bridge Biotherapeutics to jointly develop and commercialize this combined therapy. Bridge Biotherapeutics is conducting a phase 2a multinational clinical trial for the autonomic sympatho-inhibitor BBT-877, intended for the treatment of idiopathic pulmonary fibrosis (IPF), and is accelerating the development of its proprietary IPF product pipeline. About Idiopathic Pulmonary FibrosisIdiopathic Pulmonary Fibrosis (IPF) is a progressive chronic lung disease that leads to scarring (fibrosis) of the lungs, resulting in stiffening and loss of elasticity of the lung tissues, making breathing increasingly difficult. The efficiency of oxygen transfer in the lungs decreases, thus the process of oxygen passing from the alveoli to the blood during inhalation is compromised in IPF patients. The lung damage caused by IPF is irreversible, and currently, there are no treatment methods available that can stop or reverse the formation of scarring. The prognosis of Idiopathic Pulmonary Fibrosis is generally poor and the progression of the disease is difficult to predict. For some patients, the disease may progress slowly, whereas for others, it may advance more rapidly. On average, the life expectancy of patients is relatively short. Even in the United States, which has some of the world's leading medical conditions, there are approximately 495 cases per 100,000 people, with a median survival estimated at 2-5 years post-diagnosis. According to statistics from the Synapse database, there are a total of 341 R&D pipelines globally in the direction of idiopathic pulmonary fibrosis, with 4 approved drugs on the market, 6 projects in phase III clinical trials, 40 projects in phase II clinical trials, and 45 projects in phase I clinical trials. GPCR-class targets that are popular research targets for this clinical indication include autotaxin, LPAR1, αvβ6, etc. BMS-986278 is a lysophosphatidic acid receptor 1 (LPAR1) antagonist developed originally by BMS Company. Extensive research indicates that idiopathic pulmonary fibrosis (IPF) can be mediated by lysophosphatidic acid (LPA), which acts through several of the six known lysophosphatidic acid receptor-mediated downstream signaling pathways. The first generation LPAR1 antagonist developed by BMS Company, represented by BMS-986020, exhibited hepatobiliary toxicity and increased plasma bile acids in a phase II clinical trial. Subsequently, BMS Company conducted preclinical studies on the mechanism of hepatic toxicity with BMS-986020 and two structurally different LPA1 antagonists (BMS-986234 and BMS-986278), further confirming that the second-generation LPA1 antagonist BMS-986278 did not show hepatobiliary toxicity in preclinical and clinical safety studies. BMS-986278 is currently in phase II clinical development for the treatment of IPF and progressive fibrotic interstitial lung diseases. In addition to BMS, companies including Sanofi, UBE, Novo Nordisk, and DJS Antibodies have also been involved in the development of drugs targeting LPAR1 for the treatment of idiopathic pulmonary fibrosis. VP01 (C-21) is an AT2R agonist developed by Vicore Pharma. The company recently published research data demonstrating that C21 can reduce the content of TGFβ1 and collagen in human IPF lung slices. In a phase 2a clinical trial, C21 showed good safety and efficacy in newly treated IPF patients, maintaining stable forced vital capacity over a 36-week treatment period. Apart from Vicore Pharma, companies including MorphoSys and Emeriti Bio are also strategizing on the development of therapeutics targeting the AT2R for the treatment of idiopathic pulmonary fibrosis. In 2017, a team from Genentech published a research paper in the journal Thorax, discussing CXCL14 as a potential biomarker for Hedgehog signaling in idiopathic pulmonary fibrosis. Compared to the control group, there is a significant increase in the expression of Hedgehog-associated genes in the lung tissue of patients with Idiopathic Pulmonary Fibrosis (IPF). The most upregulated gene in IPF lung biopsy tissues and fibroblasts subjected to SHh stimulation in vitro was CXCL14, a gene that encodes a soluble secreted chemokine whose expression is inhibited in vitro by vismodegib. Overexpression of SHh in the lungs of mice induces the expression of CXCL14. Circulating levels of CXCL14 protein in the plasma of IPF patients are significantly higher than those in the control group. In cancer patients, circulating levels of CXCL14 decreased significantly after treatment with vismodegib. Therefore, the IL-13 inhibitor Lebrikizumab, originally developed by Genentech, is considered to have potential for the treatment of IPF. Treprostinil is a prostacyclin receptor agonist originally developed by United Therapeutics for the treatment of pulmonary arterial hypertension to alleviate exercise-related symptoms. Treprostinil is a stable, synthetic analog of prostacyclin that promotes vasodilation of the pulmonary and systemic arterial beds and inhibits platelet aggregation. It helps reduce symptoms in patients with Pulmonary Arterial Hypertension (PAH) and patients with pulmonary hypertension associated with interstitial lung disease. The FDA approved Treprostinil for the treatment of PAH in 2002. The first drug approved for the treatment of PAH was epoprostenol, an artificially synthesized prostacyclin, which significantly improves the quality of life for patients. However, the use of epoprostenol has been limited due to its short half-life (3-5 minutes) and instability at room temperature. The use of Treprostinil, a more stable alternative drug, has provided PAH patients with more treatment options. In 2021, clinical study data published in The Lancet Respiratory Medicine journal indicated that, for patients with interstitial lung disease and accompanying pulmonary arterial hypertension, inhaled Treprostinil improved patients' forced vital capacity (FVC) after 16 weeks compared to a placebo. This difference was most pronounced in patients with specific types of interstitial pneumonia, particularly those with Idiopathic Pulmonary Fibrosis. Inhaled Treprostinil appears to be a promising therapy for the treatment of Idiopathic Pulmonary Fibrosis. In 2021, multiple teams jointly initiated a phase III clinical trial of Treprostinil for the treatment of idiopathic pulmonary fibrosis. Nalbuphine is a κ-opioid receptor agonist and μ-opioid receptor antagonist that was originally researched and developed by Endo International plc. Currently, this medication is undergoing a Phase II clinical trial for Idiopathic Pulmonary Fibrosis (IPF). Brilaroxazine is a 5-HT1A/5-HT2A partial agonist originally researched and developed by Reviva Pharmaceuticals and is being used for the development of various clinical indications, including schizophrenia, idiopathic pulmonary fibrosis (IPF), and pulmonary arterial hypertension. Brilaroxazine has shown promising results in a Bleomycin-induced IPF rodent model when used alone or in combination with standard therapies. At present, this drug is also undergoing a Phase II clinical trial for IPF. Setogepram (PBI-4050) is a novel orally bioavailable small molecule compound developed by Liminal BioSciences. Its mechanism of action includes being an agonist for GPR40 and an antagonist for GPR84, demonstrating anti-fibrotic activity in various fibrosis models, including pulmonary fibrosis. Data from a 12-week Phase 2 clinical trial published in 2019 evaluated the safety, efficacy, and pharmacokinetics of daily oral administration of 800 mg of PBI-4050 alone or in combination with nintedanib or pirfenidone in patients with mild to moderate idiopathic pulmonary fibrosis (IPF). The 12-week open-label study investigated the effects of PBI-4050 in monotherapy in 9 patients, combined with nintedanib in 16 patients, and combined with nintedanib or pirfenidone in another 16 patients. The pharmacokinetic profiles were similar in both the PBI-4050 monotherapy group and the PBI-4050+nintedanib combination group, whereas the pharmacokinetics were reduced in the PBI-4050+pirfenidone group. There were no significant changes in Forced Vital Capacity (FVC) from baseline to week 12 in either the PBI-4050 monotherapy or the PBI-4050+nintedanib combination group. In contrast, a statistically significant decline in the percentage of predicted FVC was observed after 12 weeks of treatment with PBI-4050+pirfenidone. The stability of FVC between baseline and week 12 when using PBI-4050 alone or in combination with nintedanib was encouraging.