Design, synthesis, and antihypertensive evaluation of 2 '-tetrazolyl and 2 '-carboxy-biphenylylmethyl-pyrrolidine scaffolds substituted at their N-1, C-3, and C-4 positions as potential angiotensin II AT(1) receptor antagonists

作者：Ismail Mohamed A H^*; Aboul Enein Mohamed Nabil; El Azzouny Aida Abd ElSatar; Abouzid Khaled A M; Ismail Nasser S M

来源：Medicinal Chemistry Research, 2015, 24(1): 442-458.

DOI：10.1007/s00044-014-1095-9

• Ang II AT(1) antagonist
• Ang II AT(1) hypothesis
• 2 '-Tetrazolyl and 2 '-carboxy-biphenylylpyrrolidines
• Antihypertensive agent

A series of novel 2'-tetrazolyl- and 2'-carboxy-biphenylylmethyl-pyrrolidine derivatives (VIIIa-d, IX, X, XIa-d, XII, XIII, XIVa-d, XV ,and XVI) were designed and evaluated as Ang II AT(1) receptor antagonists. The compare/fit scores of these molecules were determined using an Ang II AT(1) receptor antagonist hypothesis constructed from known antagonists using CATALYST/DS modules and demonstrated significantly high simulated fit values. These hit molecules were subsequently synthesized and their in vivo antihypotensive and antihypertensive activities evaluated in normotensive cats and rats, and hypertensive rats. Compounds XII, XIII, XV, and XVI showed lower or similar levels of activity to the reference compound losartan. In contrast, the activities of compounds X and IX were 1.5- and 2-fold higher than losartan. Furthermore, the LD50 value for IX was determined to be 117 A mu g/Kg, indicating its high safety margin.

• 出版日期2015-1