新型磷酸二酯酶特異性抑制劑的發(fā)現(xiàn)及識別機制
發(fā)布時間：2018-08-14 12:10
【摘要】：磷酸二酯酶(PDE)通過催化水解細胞內(nèi)第二信使(環(huán)磷酸腺苷cAMP,或環(huán)磷酸鳥苷cGMP),以降低細胞內(nèi)cAMP或cGMP的濃度,從而中止這兩個第二信使所傳導(dǎo)的生理作用。PDEs作為新型的藥物作用靶點,參與多種疾病的治療,已成為新藥研發(fā)的重要靶點。截至目前,已有多個PDE抑制劑藥物上市(PDE5:5個,治療性功能障礙和肺動脈高壓;PDE4:3個,治療慢性阻塞性肺病等),其中最出名的案例是用于治療男性勃起功能障礙和肺動脈高壓的PDE5抑制劑西地那非。然而,低選擇性是這些PDE抑制劑的主要缺陷。近期我們針對PDE4,5,8,9和10等亞型,通過基于結(jié)構(gòu)的藥物分子設(shè)計,合成并發(fā)現(xiàn)多類高選擇性的抑制劑。如,1)合成近150個PDE9抑制劑,從中發(fā)現(xiàn)抑制效應(yīng)最強的高選擇性先導(dǎo)結(jié)構(gòu)3r。3r(IC_(50)=0.6 nmol·L~(-1),對PDE1選擇性為788倍),活性和選擇性均明顯優(yōu)于臨床Ⅱ期的輝瑞抑制劑PF-04447943。通過晶體結(jié)構(gòu)分析,發(fā)現(xiàn)3r與PDE9特有殘基Y424形成氫鍵,是其具有高倍選擇性的結(jié)構(gòu)基礎(chǔ),這為PDE9高選擇性抑制劑提供了新的設(shè)計策略。此外共晶結(jié)構(gòu)還揭示3r和A452形成一個氫鍵,而PF-04447943未顯示這種結(jié)合模式。通過設(shè)計與A452形成氫鍵,可提高化合物的抑制效應(yīng)。2)合成近100個多個PDE5抑制劑,從中發(fā)現(xiàn)抑制劑從中發(fā)現(xiàn)抑制效應(yīng)最強的高選擇性先導(dǎo)結(jié)構(gòu)1610。1610(IC_(50)=5.0 nmol·L~(-1),對PDE6選擇性為100倍)的抑制活性與輝瑞藥物西地那非相當,但選擇性均明顯優(yōu)于西地那非(對PDE6選擇性為2~3倍),動物實驗也顯示該類藥物的抗動脈高壓效果明顯優(yōu)于對照藥物西地那非。通過分子模擬分析,發(fā)現(xiàn)1610進入靶標結(jié)構(gòu)的Q2口袋,是1610具有100倍選擇性的結(jié)構(gòu)基礎(chǔ),這為PDE5高選擇性抑制劑提供了新的設(shè)計策略。
[Abstract]:Phosphodiesterase (PDE) reduces the concentration of cAMP or cGMP by catalyzing the hydrolysis of second messengers (camp, cyclic adenosine monophosphate), or guanosine cyclophosphate (cGMP), in cells. As a new drug target, PDEs is involved in the treatment of many diseases and has become an important target of new drug research and development. To date, several PDE inhibitors have been listed (PDE5: 5, PDE4: 3 for treatment of sexual dysfunction and pulmonary hypertension). One of the best known cases is sildenafil, an inhibitor of PDE5 used to treat erectile dysfunction and pulmonary hypertension in men. However, low selectivity is the main defect of these PDE inhibitors. Recently, we synthesized and discovered many kinds of highly selective inhibitors by structure-based drug molecular design for PDE4C5H8 / 9 and PDE4 / 10 subtypes. If 1) nearly 150 PDE9 inhibitors were synthesized, the highly selective leading structure 3r.3r (IC50) 0.6 nmol L ~ (-1) was found to have the strongest inhibitory effect, and the selectivity to PDE1 was 788-fold. The activity and selectivity of Pfizer inhibitor Pfizer (PF-04447943) were significantly better than that of Pfizer inhibitor Pfizer in phase 鈪，
本文編號：2182820
[Abstract]:Phosphodiesterase (PDE) reduces the concentration of cAMP or cGMP by catalyzing the hydrolysis of second messengers (camp, cyclic adenosine monophosphate), or guanosine cyclophosphate (cGMP), in cells. As a new drug target, PDEs is involved in the treatment of many diseases and has become an important target of new drug research and development. To date, several PDE inhibitors have been listed (PDE5: 5, PDE4: 3 for treatment of sexual dysfunction and pulmonary hypertension). One of the best known cases is sildenafil, an inhibitor of PDE5 used to treat erectile dysfunction and pulmonary hypertension in men. However, low selectivity is the main defect of these PDE inhibitors. Recently, we synthesized and discovered many kinds of highly selective inhibitors by structure-based drug molecular design for PDE4C5H8 / 9 and PDE4 / 10 subtypes. If 1) nearly 150 PDE9 inhibitors were synthesized, the highly selective leading structure 3r.3r (IC50) 0.6 nmol L ~ (-1) was found to have the strongest inhibitory effect, and the selectivity to PDE1 was 788-fold. The activity and selectivity of Pfizer inhibitor Pfizer (PF-04447943) were significantly better than that of Pfizer inhibitor Pfizer in phase 鈪，
本文編號：2182820
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