The alternative pathway (AP) of the complement system is a key contributor to the pathogenesis of several human diseases including age-related macular degeneration, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and various glomerular diseases. The serine protease factor B (FB) is a key node in the AP and is integral to the formation of C3 and C5 convertase. Despite the prominent role of FB in the AP, selective orally bioavailable inhibitors, beyond our own efforts, have not been reported previously. Herein we describe in more detail our efforts to identify FB inhibitors by high-throughput screening (HTS) and leveraging insights from several X-ray cocrystal structures during optimization efforts. This work culminated in the discovery of LNP023 (41), which is currently being evaluated clinically in several diverse AP mediated indications.

中文翻译：

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发现4-（（2S，4S）-4-乙氧基-1-（（5-甲氧基-7-甲基-1H-吲哚-4-基）甲基）哌啶-2-基）苯甲酸（LNP023）专门设计用于治疗多种补体介导疾病的因子B抑制剂。

补体系统的替代途径（AP）是几种人类疾病发病机理的关键因素，包括与年龄有关的黄斑变性，阵发性夜间血红蛋白尿（PNH），非典型溶血性尿毒症综合征（aHUS）和各种肾小球疾病。丝氨酸蛋白酶因子B（FB）是AP中的关键节点，对于C3和C5转化酶的形成必不可少。尽管FB在AP中起着重要的作用，但是迄今为止，我们还没有报道过选择性的口服生物利用抑制剂，这超出了我们的努力。在这里，我们将更详细地描述我们通过高通量筛选（HTS）鉴定FB抑制剂的努力，并在优化工作中利用来自多个X射线共晶结构的见解。这项工作最终导致发现LNP023（41），目前正在多种AP介导的适应症中对其进行临床评估。