Antifibrotic Therapy for the Treatment of Pulmonary Hypertension

松弛素最初被发现是一种妊娠激素；促进心血管和肾脏调整，以满足不断增长的胎儿日益增长的营养需求，提高对肾脏清除代谢废物的要求，以及放松平滑肌和韧带以促进分娩。松弛素样家族多肽受体1(RXFP1)在松弛素刺激下既有抗纤维化作用，又有血管扩张作用。虽然重组松弛素已在临床上用于治疗各种疾病，但其较短的半衰期和静脉给药要求阻碍了其长期使用。 为了绕过这些限制，主要合作者已经确定了一种合成的RXFP1小分子激动剂(ML290)作为松弛激素的替代品。在化学诱导的纤维化动物模型中，ML290被证明可以逆转纤维化损伤。在第二种低氧条件下的PAH动物模型中，ML290被证明可以降低右室收缩压，并在腹腔注射后减轻右室肥厚。这些观察结果支持了ML290可用于治疗特发性肺纤维化患者PAH的假设。TRND的科学家们已经发起了一项药物化学活动，以优化ML290，目标是开发一种在口服后在小鼠体内活跃的新铅。

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.