Y-shaped bis-arylethenesulfonic acid esters: Potential potent and membrane permeable protein tyrosine phosphatase 1B inhibitors |
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Authors: | Fengzhi Yang Fangzhou Xie Ying Zhang Yu Xia Wenlu Liu Faqin Jiang Celine Lam Yixue Qiao Dongsheng Xie Jianqi Li Lei Fu |
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Affiliation: | 1. School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, PR China;2. China State Institute of Pharmaceutical Industry, Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, Shanghai 201203, PR China;3. Viva Biotech (Shanghai) Limited, Shanghai 201203, PR China |
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Abstract: | Known PTP1B inhibitors with bis-anionic moieties exhibit potent inhibitory activity, good selectivity, however, they are incapable of penetrating cellular membranes. Based upon our finding of a new pharmacophoric group in inhibition of PTP1B and the structural characteristics of the binding pocket of PTP1B, a series of bis-arylethenesulfonic acid ester derivatives were designed and synthesized. These novel molecules, particularly Y-shaped bis-arylethenesulfonic acid ester derivatives, exhibited high PTP1B inhibitory activity, moderate selectivity, and great potential in penetrating cellular membranes (compound 7p, CLog P = 9.73, Papp = 9.6 × 10-6 cm/s; IC50 = 140, 1290 and 920 nM on PTP1B, TCPTP and SHP2, respectively). Docking simulations suggested that these Y-shaped inhibitors might interact with multiple secondary binding sites in addition to the catalytic site of PTP1B. |
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Keywords: | Type 2 diabetes PTP1B inhibitors Phosphotyrosine mimics Arylethenesulfonic acid esters |
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