The highly specific S1 serine protease factor D (FD) plays a central role in the amplification of the complement alternative pathway (AP) of the innate immune system. Genetic associations in humans have implicated AP activation in age-related macular degeneration (AMD), and AP dysfunction predisposes individuals to disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). The combination of structure-based hit identification and subsequent optimization of the center (S)-proline-based lead 7 has led to the discovery of noncovalent reversible and selective human factor D (FD) inhibitors with drug-like properties. The orally bioavailable compound 2 exerted excellent potency in 50% human whole blood in vitro and blocked AP activity ex vivo after oral administration to monkeys as demonstrated by inhibition of membrane attack complex (MAC) formation. Inhibitor 2 demonstrated sustained oral and ocular efficacy in a model of lipopolysaccharide (LPS)-induced systemic AP activation in mice expressing human FD.

中文翻译：

---

发现高活性和选择性的小分子可逆因子D抑制剂，表明体内有替代补体途径抑制作用

高特异性的S1丝氨酸蛋白酶因子D（FD）在先天免疫系统的补体替代途径（AP）的扩增中起着核心作用。人类的遗传关联暗示了AP激活与年龄相关的黄斑变性（AMD），并且AP功能障碍使个体容易患上阵发性夜间血红蛋白尿（PNH）和非典型溶血性尿毒症综合征（aHUS）等疾病。基于结构的命中鉴定和随后基于中心（S）-脯氨酸的前导物7的优化相结合，导致发现了具有药物样特性的非共价可逆和选择性人因子D（FD）抑制剂。口服可生物利用的化合物2在50％的人类全血中发挥了出色的功效口服和猴子体外给药后体外抑制AP活性，这是通过抑制膜攻击复合物（MAC）的形成证明的。在表达人FD的小鼠中，脂多糖（LPS）诱导的全身性AP活化模型中，抑制剂2表现出持续的口服和眼部功效。