Design, Synthesis, and Biological Evaluation of Indoline and Indole Derivatives as Potent and Selective α_1A-Adrenoceptor Antagonists

A series of indoline and indole derivatives were designed, synthesized, and evaluated as selective α1A-adrenergic receptor (α1A-AR) antagonists for the treatment of benign prostatic hyperplasia (BPH). In this study, two highly selective and potent α1A-AR antagonists, compounds (R)-14r (IC50 = 2.7 nM, α1B/α1A = 640.1, α1D/α1A = 408.2) and (R)-23l (IC50 = 1.9 nM, α1B/α1A = 1506, α1D/α1A = 249.6), which exhibited similar activities and better selectivities in cell-based calcium assays as compared with the marketed drug silodosin (IC50 = 1.9 nM, α1B/α1A = 285.9, α1D/α1A = 14.4), were identified. In the functional assays with isolated rat tissues, compounds (R)-14r and (R)-23l also showed high potency and uroselectivity. Most importantly, (R)-14r and (R)-23l can significantly decrease the micturition frequency and increase the mean voided volume of the BPH rats in a dose-dependent manner, making them worthy of further investigation for the development of anti-BPH agents.本研究设计、合成并评价了一系列吲哚啉（indoline）与吲哚（indole）衍生物，将其作为选择性α1A肾上腺素能受体（α1A-AR）拮抗剂用于良性前列腺增生（BPH）的治疗。本研究中，研究者筛选得到两个兼具高选择性与强效活性的α1A-AR拮抗剂：化合物(R)-14r（半数抑制浓度IC50=2.7 nM，α1B/α1A=640.1，α1D/α1A=408.2）与(R)-23l（IC50=1.9 nM，α1B/α1A=1506，α1D/α1A=249.6）。相较于上市药物西洛多辛（IC50=1.9 nM，α1B/α1A=285.9，α1D/α1A=14.4），二者在细胞钙检测实验中展现出相当的活性及更优的选择性。在离体大鼠组织功能实验中，(R)-14r与(R)-23l同样表现出强效与尿路选择性。尤为关键的是，(R)-14r和(R)-23l可呈剂量依赖性显著降低BPH模型大鼠的排尿频率，并提升其平均排尿量，因此具备作为抗BPH药物进一步开发的价值。