Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, UT of J&K, India.
Academy of Scientific and Innovative Research, Ghaziabad, 201002, Uttar Pradesh, India.
Chem Biodivers. 2023 Apr;20(4):e202200707. doi: 10.1002/cbdv.202200707. Epub 2023 Mar 24.
Continuing research with our earlier finding of sildenafil based analogs in the search of new inhibitors of PDE5 for erectile dysfunction suggested that there is a scope of modifications at N-methylpiperazine ring with hydrophobic region followed by hydrogen bond donor or acceptor region. However, the leads identified earlier had some limitations like poor pharmacokinetic (PK) profile, low aqueous solubility and poor bioavailability. In this direction, a new series of sildenafil based analogs were designed, synthesized and screened for their PDE5 inhibitory activity. In this series compound 18 was found to have excellent in vitro activity with selectivity towards PDE5 isozyme, also the in vivo activity and pharmacokinetic profile was excellent. The cyp inhibition and CaCO permeability was also excellent for compound 18.
在对我们早期发现的用于治疗勃起功能障碍的磷酸二酯酶 5（PDE5）抑制剂的西地那非类似物进行进一步研究时，我们发现 N-甲基哌嗪环上存在进一步修饰的空间，可以引入疏水区域，随后是氢键供体或受体区域。然而，之前确定的先导化合物存在一些局限性，例如药代动力学（PK）特性不佳、水溶解度低和生物利用度差。在这一方向上，我们设计、合成了一系列新的西地那非类似物，并对其磷酸二酯酶 5 抑制活性进行了筛选。在这个系列中，化合物 18 被发现具有优异的体外活性，对 PDE5 同工酶具有选择性，同时体内活性和药代动力学特性也非常出色。化合物 18 的 CYP 抑制作用和 CaCO 通透性也非常好。
