Ahmed Nermin S
Faculty of Pharmacy and Biotechnology, Department of Pharmaceutical Chemistry, German University in Cairo, Cairo, Egypt.
Drug Dev Res. 2018 Dec 13. doi: 10.1002/ddr.21493.
Hit, Lead & Candidate Discovery Tadalafil, Cialis, Eli Lilly & Co./ICOS, (6R,12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6] pyrido[3,4-b]indole-1,4-dione, was first discovered in 2003. It was reported to have high diastereospecificity for phosphodiesterase 5 (PDE5) inhibitions. The cis-(6R, 12aR) enantiomer is the most active enantiomer. Tadalafil showed PDE5 inhibition with IC = 5 nM. It possesses high selectivity for PDE5 versus PDE1-4 and PDE6. Tadalafil is more selective to PDE5 against PDE6 whereas sildenafil, another commercially available PDE5 inhibitor shows similar potencies to inhibit PDE5 and PDE6. Tadalafil is used for the treatment of male erectile dysfunction (MED), prostatic benign hyperplasia (PBH) signs and symptoms, and pulmonary arterial hypertension (PAH). Adcirca, another name for tadalafil, is used to treat PAH and improve exercise capacity. Recent clinical studies suggest the use of tadalafil for nonurological applications, including circulatory disorders (ischemia injury, myocardial infarction, cardiac hypertrophy, cardiomyopathy, heart failure, and stroke), neurodegenerative disorders, and cognitive impairment conditions. This review discusses tadalafil and its analogues reported in the past 15 years. It discusses synthetic pathways, structural activity relationships, existing and future pharmacological indications of tadalafil and its analogues. This work can help medicinal chemists developing novel PDE5 inhibitors with wider therapeutic indications.
命中、先导及候选药物发现 他达拉非，商品名希爱力，礼来公司/ICOS公司，化学名为(6R,12aR)-6-(1,3-苯并二氧杂环戊烯-5-基)-2-甲基-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，于2003年首次被发现。据报道，它对磷酸二酯酶5（PDE5）抑制具有高非对映体选择性。顺式-(6R,12aR)对映体是活性最高的对映体。他达拉非对PDE5的抑制作用的IC50为5 nM。它对PDE5相对于PDE1 - 4和PDE6具有高选择性。与另一种市售的PDE5抑制剂西地那非相比，他达拉非对PDE5比对PDE6更具选择性，而西地那非抑制PDE5和PDE6的效力相似。他达拉非用于治疗男性勃起功能障碍（MED）、前列腺良性增生（PBH）的体征和症状以及肺动脉高压（PAH）。他达拉非的另一个名称Adcirca用于治疗PAH并改善运动能力。最近的临床研究表明他达拉非可用于非泌尿系统应用，包括循环系统疾病（缺血性损伤、心肌梗死、心脏肥大、心肌病、心力衰竭和中风）、神经退行性疾病和认知障碍病症。本综述讨论了过去15年报道的他达拉非及其类似物。它讨论了他达拉非及其类似物的合成途径、构效关系、现有和未来的药理学适应症。这项工作有助于药物化学家开发具有更广泛治疗适应症的新型PDE5抑制剂。
