Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt.
J Med Chem. 2011 Jan 27;54(2):495-509. doi: 10.1021/jm100842v. Epub 2010 Dec 28.
New derivatives based upon the tetrahydro-β-carboline-hydantoin and tetrahydro-β-carboline-piperazinedione scaffolds were synthesized. All compounds were evaluated for their ability to inhibit PDE5 in vitro, and numerous compounds with IC(50) values in the low nanomolar range were identified including compounds derived from l-tryptophan. Compounds with high potency versus PDE5 were then evaluated for inhibitory activity against other PDEs to assess isozyme selectivity. Compound 5R,11aS-5-(3,4-dichlorophenyl)-2-ethyl-5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)dione 14 showed a selectivity index of >200 for cGMP hydrolysis by PDE5 versus PDE11. Meanwhile, 6R,12aR-6-(2,4-dichlorophenyl)-2-ethyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4dione 45 demonstrated strong potency for inhibition of PDE11 with an IC(50) value of 11 nM, representing the most potent PDE11 inhibitor thus far reported. Docking experiments differentiated between active and inactive analogues and revealing the conformational, steric, and lipophilic necessities for potent PDE5 inhibition. Many derivatives, including potent PDE5 inhibitors, were able to inhibit the growth of the MDA-MB-231 breast tumor cell line with low micromolar potency.
合成了基于四氢-β-咔啉-海因和四氢-β-咔啉-哌嗪二酮骨架的新衍生物。所有化合物均进行了体外抑制 PDE5 的能力评估，鉴定出了许多具有低纳摩尔范围内 IC50 值的化合物，包括来源于 l-色氨酸的化合物。然后，对具有高 PDE5 抑制活性的化合物进行了对其他 PDEs 的抑制活性评估，以评估同工酶选择性。化合物 5R,11aS-5-(3,4-二氯苯基)-2-乙基-5,6,11,11a-四氢-1H-咪唑并[1',5':1,6]吡啶并[3,4-b]吲哚-1,3(2H)二酮 14 对 PDE5 催化的 cGMP 水解的选择性指数大于 200，而 6R,12aR-6-(2,4-二氯苯基)-2-乙基-2,3,6,7,12,12a-六氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮 45 对 PDE11 的抑制作用具有很强的活性，IC50 值为 11 nM，是迄今为止报道的最有效的 PDE11 抑制剂。对接实验区分了活性和非活性类似物，并揭示了对 PDE5 抑制活性的构象、空间和疏水性的需求。许多衍生物，包括有效的 PDE5 抑制剂，能够以低微摩尔的效力抑制 MDA-MB-231 乳腺癌细胞系的生长。
