Antifibrotic Therapy for the Treatment of Pulmonary Hypertension

松弛素最初被发现作为一种怀孕激素;促进心血管和肾脏的调整，以满足不断增长的胎儿的营养需求增加，代谢废物的肾脏清除需求增加，以及平滑肌和韧带的松弛，以促进劳动和交付。松弛素/胰岛素样家族肽受体1（RXFP 1）在被松弛素刺激时具有抗纤维化和血管舒张作用。虽然重组松弛素已在临床上用于各种疾病，但其短半衰期和静脉内递送的要求对长期使用造成障碍。 为了克服这些限制，主要合作者已经确定了RXFP 1（ML 290）的合成小分子激动剂作为松弛素激素的替代品。在化学诱导纤维化的动物模型中，ML 290显示出逆转纤维化损伤。在缺氧条件性PAH的第二种动物模型中，ML 290显示在腹膜内给药后降低右心室收缩压并减弱右心室肥大。这些观察结果支持ML 290可用于治疗特发性肺纤维化患者的PAH的假设。TRND的科学家们发起了一项药物化学活动，以优化ML 290，目标是开发一种口服后在小鼠中具有活性的新先导化合物。

Relaxin was originally discovered as a hormone of pregnancy; promoting cardiovascular and renal adjustments to meet the increased nutritional demands of the growing fetus, the elevated requirements for renal clearance of metabolic wastes, and the relaxation of smooth muscle and ligaments to facilitate labor and delivery. The relaxin/insulin-like family peptide receptor 1 (RXFP1) has both antifibrotic and vasodilatory effects when stimulated by relaxin. While recombinant relaxin has been explored clinically for various diseases, its short half-life and requirement for intravenous delivery present obstacles for longer-term use. To circumvent these limitations, the lead collaborators have identified a synthetic small molecule agonist of RXFP1 (ML290) as an alternative to relaxin hormone. In an animal model of chemically-induced fibrosis, ML290 was shown to reverse fibrotic damage. In a second animal model of hypoxia-conditioned PAH, ML290 was shown to reduce right ventricular systolic pressure and attenuate right ventricular hypertrophy after intraperitoneal administration. These observations support the hypothesis that ML290 could be useful to treat PAH in patients with idiopathic pulmonary fibrosis. TRND scientists have initiated a medicinal chemistry campaign to optimize ML290, with the goal of developing a new lead that is active in the mouse after oral administration.