Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt.
Arch Pharm (Weinheim). 2013 Jan;346(1):23-33. doi: 10.1002/ardp.201200334.
New derivatives with the tetrahydro-β-carboline-imidazolidinedione and tetrahydro-β-carboline-piperazinedione scaffolds and a pendant bromothienyl moiety at C-5/C-6 were synthesized and tested for their ability to inhibit PDE5 in vitro. The following SAR can be concluded: The tetracyclic scaffold is essential for PDE5 inhibition; the ethyl group is the most suitable among the adopted N-substituents on the terminal ring (hydantoin/piperazinedione); the appropriate stereochemistry of C-5/C-6 derived from the aldehyde rather than C-11a/C-12a derived from tryptophan appears crucial for inhibition of PDE5; surprisingly, derivatives with the hydantoin terminal ring are more active than their analogs with the piperazinedione ring; the selectivity versus PDE5 relative to PDE11 with cGMP as a substrate is mainly a function of the substitution and stereochemistry pattern of the external ring, in other words of the interaction with the H-loop residues of the isozymes. Thirteen derivatives showed PDE5 inhibitory activity with IC(50) values in the range of 0.16-5.4 µm. Compound 8 was the most potent PDE5 inhibitor and showed selectivity towards PDE5 versus other PDEs, with a selectivity index of 49 towards PDE5 rather than PDE11 with cGMP as the substrate.
新的具有四氢-β-咔啉-咪唑烷二酮和四氢-β-咔啉-哌嗪二酮骨架的衍生物，以及在 C-5/C-6 位置带有溴噻吩部分的侧链，被合成并测试了它们在体外抑制 PDE5 的能力。可以得出以下 SAR：四环骨架对于 PDE5 抑制是必需的；在末端环上采用的 N-取代基中，乙基是最合适的（海因/哌嗪二酮）；来自醛的 C-5/C-6 的合适立体化学，而不是来自色氨酸的 C-11a/C-12a，对于抑制 PDE5 似乎至关重要；令人惊讶的是，具有海因末端环的衍生物比具有哌嗪二酮环的类似物更具活性；与 PDE11 相比，以 cGMP 为底物时对 PDE5 的选择性主要是外环取代和立体化学模式的函数，换句话说，是与同工酶的 H-环残基相互作用的函数。有 13 种衍生物表现出 PDE5 抑制活性，IC50 值在 0.16-5.4µm 范围内。化合物 8 是最有效的 PDE5 抑制剂，对 PDE5 具有选择性，与以 cGMP 为底物的 PDE11 相比，对 PDE5 的选择性指数为 49。
