Discovery of trisubstituted pyrazolines as a novel scaffold for the development of selective phosphodiesterase 5 inhibitors.
Discovery of trisubstituted pyrazolines as a novel scaffold for the development of selective phosphodiesterase 5 inhibitors.
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DOI：
10.1016/j.bioorg.2020.104322
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发表时间：
2020-11
影响因子：
5.1
通讯作者：
Abadi AH
中科院分区：
文献类型：
--
作者：
Abdel-Halim M;Tinsley H;Keeton AB;Weam M;Atta NH;Hammam MA;Hefnawy A;Hartmann RW;Engel M;Piazza GA;Abadi AH
塞来昔布是一种具有1，5-二芳基吡唑骨架的选择性环氧合酶-2（COX 2）抑制剂。塞来昔布的安全性优于其他具有全身性高血压和血栓栓塞并发症副作用的COX 2抑制剂。这可能部分归因于涉及磷酸二酯酶5（PDE 5）抑制和NO/cGMP信号传导增强的脱靶活性，从而允许冠状血管舒张和主动脉舒张。受塞来昔布结构的启发，我们合成了一系列化学上不同的化合物，其中含有1，3，5-三取代吡唑啉骨架，以提高PDE 5抑制效力，同时消除COX 2抑制活性。PDE 5抑制的SAR研究揭示了1-苯基处的羧酸官能团的重要作用以及非平面吡唑啉核心相对于平面吡唑的重要性，其中5-苯基部分耐受一系列取代基。这些修饰导致新的PDE 5抑制剂与塞来昔布相比，抑制PDE 5的效力提高约20倍，并且没有考克斯-2抑制活性。化合物11的PDE同工酶谱显示了有利的选择性谱。这些结果表明，三取代的吡唑啉类化合物为进一步的化学优化提供了一个有前途的支架，以鉴定与用于治疗阴茎勃起功能障碍和肺动脉高压的现有PDE 5抑制剂相比具有更少副作用的新型PDE 5抑制剂。
Celecoxib, is a selective cyclooxygenase-2 (COX2) inhibitor with a 1,5-diaryl pyrazole scaffold. Celecoxib has a better safety profile compared to other COX2 inhibitors having side effects of systemic hypertension and thromboembolic complications. This may be partly attributed to an off-target activity involving phosphodiesterase 5 (PDE5) inhibition and the potentiation of NO/cGMP signalling allowing coronary vasodilation and aortic relaxation. Inspired by the structure of celecoxib, we synthesized a chemically diverse series of compounds containing a 1,3,5-trisubstituted pyrazoline scaffold to improve PDE5 inhibitory potency, while eliminating COX2 inhibitory activity. SAR studies for PDE5 inhibition revealed an essential role for a carboxylic acid functionality at the 1-phenyl and the importance of the non-planar pyrazoline core over the planar pyrazole with the 5-phenyl moiety tolerating a range of substituents. These modifications led to new PDE5 inhibitors with approximately 20-fold improved potency to inhibit PDE5 and no COX-2 inhibitory activity compared with celecoxib. PDE isozyme profiling of compound 11 revealed a favorable selectivity profile. These results suggest that trisubstituted pyrazolines provide a promising scaffold for further chemical optimization to identify novel PDE5 inhibitors with potential for less side effects compared with available PDE5 inhibitors used for the treatment of penile erectile dysfunction and pulmonary hypertension.
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影响因子：
3.4
作者：
Ballatore, Carlo;Huryn, Donna M.;Smith, Amos B., III
通讯作者：
Smith, Amos B., III
DOI：
10.1038/nrd2030
发表时间：
2006-08
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Ghofrani HA;Osterloh IH;Grimminger F
通讯作者：
Grimminger F
影响因子：
6.7
作者：
Abadi AH;Gary BD;Tinsley HN;Piazza GA;Abdel-Halim M
通讯作者：
Abdel-Halim M
影响因子：
3.8
作者：
DIMMOCK, JR;KIRKPATRICK, DL;CROSS, BM
通讯作者：
CROSS, BM
影响因子：
1.7
作者：
Esen, Ilker;Yolacan, Cigdem;Aydogan, Feray
通讯作者：
Aydogan, Feray