2-Amino-1,3,4-thiadiazoles in the 7-hydroxy-N-neopentyl spiropiperidine indolinyl series as potent P2Y₁ receptor antagonists

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• 作者：Carol H. Hu ; ^{carol.hu@bms.com" class="auth_mail} ; Jennifer X. Qiao ; ^{jennifer.qiao@bms.com" class="auth_mail} ; Ying Han ; Tammy C. Wang ; Ji Hua ; Laura A. Price ; Qimin Wu ; Hong Shen ; Christine S. Huang ; Robert Rehfuss ; Ruth R. Wexler ; Patrick Y.S. Lam
• 关键词：P2Y1 receptor antagonist ; Antiplatelet ; Urea mimetics ; 2-Amino-1 ; 3 ; 4-thiadiazoles ; Structure&ndash ; activity relationship (SAR)
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：1 June 2014
• 年：2014
• 卷：24
• 期：11
• 页码：2481-2485
• 全文大小：1511 K

文摘

Blockade of the P2Y₁ receptor is important to the treatment of thrombosis with potentially improved safety margins compared with P2Y₁₂ receptor antagonists. Investigation of a series of urea surrogates of the diaryl urea lead 3 led to the discovery of 2-amino-1,3,4-thiadiazoles in the 7-hydroxy-N-neopentyl spiropiperidine indolinyl series as potent P2Y₁ receptor antagonists, among which compound 5a was the most potent and the first non-urea analog with platelet aggregation (PA) IC₅₀ less than 0.5 渭M with 10 渭M ADP. Several 2-amino-1,3,4-thiadiazole analogs such as 5b and 5f had a more favorable pharmacokinetic profile, such as higher C_trough, lower Cl, smaller V_dss, and similar bioavailability compared with 3.