Jain Priti, Wadhwa Pankaj K, Jadhav Hemant R
Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi, India.
Medicinal Chemistry Laboratory, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333 031, India.
Med Chem. 2021;17(10):1194-1206. doi: 10.2174/1573406417666201221155452.
Alzheimer's disease is one of the most common neurodegenerative disorder afflicting a large mass of population. BACE-1 (β-secretase) is an aspartyl protease of the amyloidogenic pathway considered responsible for Alzheimer's disease (AD). Since it catalyzes the rate-limiting step of Aβ-42 production from amyloid precursor protein (APP), its inhibition is considered a viable therapeutic strategy. We have reported the design of small molecular weight compounds supposed to be blood brain permeable as BACE-1 inhibitors. The clue for the design of this series is drawn from the previously designed series from our research group.
Design and synthesis of 2,4,6-substituted pyrimidine derivatives has been reported. In vitro FRET-based screening of synthesized derivatives was performed to evaluate the BACE-1 inhibition profile.
Based on the docking simulation studies, a library of derivatives was designed, synthesized and evaluated for BACE-1 inhibition in-vitro. The docking studies were performed on Glide (Schrodinger suite) and Molegro virtual docker. Theoretical toxicity was predicted using Osiris Property Explorer. The synthesized compounds were tested for BACE-1 inhibition using in vitro assay based on Fluorescence Resonance Energy Transfer technique. The percent inhibition was calculated as a measure of activity.
The designed compounds revealed strong interactions with the desired amino acids of BACE-1 active sites. The aromatic rings placed at the fourth and sixth position of the pyrimidine ring occupied S1 and S3 substrate-binding clefts while the amino group formed hydrogen bonding interactions with Asp32 and Asp228. In silico data ensured that the compounds were orally bioavailable and brain permeable. The in vitro testing showed that the compounds inhibited BACE-1 at 10μM concentration.
Compounds substituted with m-benzyloxy on one aromatic ring and o,p-di-chloro on another aromatic ring displayed maximum BACE-1 inhibition. Compound 2.13A displayed high docking score and was found to be most potent with IC of 6.92μM. The series displayed a good correlation between the docking score and BACE-1 inhibition profile.
阿尔茨海默病是困扰大量人群的最常见神经退行性疾病之一。β-分泌酶1（BACE-1）是淀粉样蛋白生成途径中的一种天冬氨酸蛋白酶，被认为与阿尔茨海默病（AD）有关。由于它催化淀粉样前体蛋白（APP）生成Aβ-42的限速步骤，其抑制作用被认为是一种可行的治疗策略。我们已经报道了设计出的小分子化合物，它们被认为可作为BACE-1抑制剂透过血脑屏障。该系列化合物设计的线索来自我们研究小组之前设计的系列。
已报道了2,4,6-取代嘧啶衍生物的设计与合成。对合成的衍生物进行了基于荧光共振能量转移（FRET）的体外筛选，以评估其对BACE-1的抑制情况。
基于对接模拟研究，设计、合成了一系列衍生物，并对其体外抑制BACE-1的活性进行评估。对接研究在Glide（薛定谔套件）和Molegro虚拟对接软件上进行。使用奥西里斯性质探索者预测理论毒性。使用基于荧光共振能量转移技术的体外试验检测合成化合物对BACE-1的抑制作用。计算抑制百分比作为活性的衡量指标。
设计的化合物与BACE-1活性位点的目标氨基酸显示出强烈的相互作用。位于嘧啶环第四和第六位的芳环占据S1和S3底物结合裂隙，而氨基与Asp32和Asp228形成氢键相互作用。计算机模拟数据确保这些化合物具有口服生物利用度且可透过血脑屏障。体外试验表明，这些化合物在10μM浓度下可抑制BACE-1。
一个芳环上被间苄氧基取代且另一个芳环上被邻、对二氯取代的化合物对BACE-1的抑制作用最强。化合物2.13A显示出高对接分数，被发现最有效，IC50为6.92μM。该系列在对接分数和BACE-1抑制情况之间显示出良好的相关性。
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