ADME studies and preliminary safety pharmacology of LDT5, a lead compound for the treatment of benign prostatic hyperplasia

This study aimed to estimate the absorption, distribution, metabolism and excretion (ADME) properties and safety of LDT5, a lead compound for oral treatment of benign prostatic hyperplasia that has previously been characterized as a multi-target antagonist of α1A-, α1D-adrenoceptors and 5-HT1A receptors. The preclinical characterization of this compound comprised the evaluation of its in vitro properties, including plasma, microsomal and hepatocytes stability, cytochrome P450 metabolism and inhibition, plasma protein binding, and permeability using MDCK-MDR1 cells. De-risking and preliminary safety pharmacology assays were performed through screening of 44 off-target receptors and in vivo tests in mice (rota-rod and single dose toxicity). LDT5 is stable in rat and human plasma, human liver microsomes and hepatocytes, but unstable in rat liver microsomes and hepatocytes (half-life of 11 min). LDT5 is highly permeable across the MDCK-MDR1 monolayer (Papp ∼32×10-6 cm/s), indicating good intestinal absorption and putative brain penetration. LDT5 is not extensively protein-bound and is a substrate of human CYP2D6 and CYP2C19 but not of CYP3A4 (half-life >60 min), and did not significantly influence the activities of any of the human cytochrome P450 isoforms screened. LDT5 was considered safe albeit new studies are necessary to rule out putative central adverse effects through D2, 5-HT1A and 5-HT2B receptors, after chronic use. This work highlights the drug-likeness properties of LDT5 and supports its further preclinical development.

本研究旨在评估LDT5的吸收、分布、代谢与排泄（ADME）特性及安全性，LDT5是一款用于治疗良性前列腺增生的口服先导化合物，此前已被表征为α1A、α1D肾上腺素能受体及5-HT1A受体的多靶点拮抗剂。该化合物的临床前表征工作涵盖其体外特性评价，包括血浆、微粒体及肝细胞稳定性，细胞色素P450代谢与抑制特性，血浆蛋白结合率，以及使用MDCK-MDR1细胞进行的通透性检测。本研究通过针对44个脱靶受体的筛选以及小鼠体内实验（转棒实验与单次给药毒性试验）完成了风险降低与初步安全药理学评估。实验结果显示，LDT5在大鼠及人血浆、人肝微粒体和肝细胞中稳定性良好，但在大鼠肝微粒体及肝细胞中稳定性较差（半衰期为11分钟）。LDT5可高效透过MDCK-MDR1单层细胞（表观渗透系数Papp约为32×10⁻⁶ cm/s），提示其具备良好的肠道吸收能力及潜在的脑内穿透性。LDT5蛋白结合率较低，为人类CYP2D6及CYP2C19的底物，但并非CYP3A4的底物（半衰期＞60分钟），且对所筛选的所有人类细胞色素P450同工酶活性均无显著影响。尽管仍需开展新研究以排除长期给药后通过D2、5-HT1A及5-HT2B受体引发潜在中枢不良反应的可能，但LDT5整体安全性良好。本研究证实了LDT5的成药性特征，为其后续临床前开发提供了有力支持。