Novel Dual Inhibitors of Secretory Phospholipase A2 and Sphingomyelin Synthase: Design, Synthesis and Evaluation

Atherosclerosis is a fatal disease for decades, which was thought to be the basis onset of many other cardiovascular diseases. Its pathogenesis is complex, mainly for the chronic vascular inflammation symptoms caused by abnormal lipid metabolism. Inflammation has been recognized as the pivotal role during every step of atherosclerosis. In view of the complication of its pathogenic process, the multi-target medication sometimes is more effective, less side effect and could reduce tolerance which should be another reasonable strategy for anti-atherosclerosis. Sphingomyelin synthase (SMS) is a potential therapeutic target for atherosclerosis treatment, while secretory phospholipase A2 (sPLA2) have been studied as a target of atherosclerosis treatment which plays an important role in the genesis and development of its progress of atherosclerosis. Based on the complex pathogenesis of atherosclerosis, we focused on two key enzymes in this process—SMS and sPLA2. We combined with the existing QSAR of the inhibitors of SMS and sPLA2 and rational multi-target drug design ideas, three series of dual inhibitors of sPLA2 and SMS were designed by linking or fusing SMS inhibitor fragment Ly18 (N-pyridine-3-amide moiety) with sPLA2 inhibitor fragment (indole- 3-acetamide structure) by 3-6 carbon chain as novel dual-functional inhibitors series 1-3. Series 2 and 3 reserved benzyl in sPLA2 or SMS pharmacophore respectively, while series 1 was de-benzyl in order to decrease the molecular weight. Eleven target molecules were synthesized and bio-assayed in vitro. The results showed compounds 3a-3d provided inhibitory activities against SMS2 and 2a-2d exhibited the sPLA2 inhibition activities. The compound 3c showed equivalent activities of both SMS and sPLA2 which would be a potential leading compound of dual inhibitor against atherosclerosis.