Design, synthesis and evaluation of novel potent angiotensin II receptor 1 antagonists

• Published in: European journal of medicinal chemistry Vol. 123; pp. 115 - 127
• Main Authors: Bao, Xiaolu, Zhu, Weibo, Yuan, Weidong, Zhu, Xingbo, Yan, Yijia, Tang, Hesheng, Chen, Zhilong
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 10.11.2016; Elsevier
• Subjects: Angiotensin II Type 1 Receptor Blockers - chemical synthesis; Angiotensin II Type 1 Receptor Blockers - chemistry; Angiotensin II Type 1 Receptor Blockers - pharmacology; Animals; Antihypertensive Agents - chemistry; Antihypertensive Agents - pharmacokinetics; Antihypertensive Agents - pharmacology; ARBs; Blood Pressure - drug effects; Chemistry, Medicinal; Drug Design; Hypertension; Life Sciences & Biomedicine; Pharmacokinetic; Pharmacology & Pharmacy; Rats; Rats, Inbred SHR; Rats, Wistar; Receptor, Angiotensin, Type 1 - metabolism; Science & Technology; Structure-Activity Relationship; Tissue Distribution; Hypertension; Tissue distribution; ARBs; Pharmacokinetic; BLOCKERS; PHARMACOKINETICS; SAFETY; BIOLOGICAL EVALUATION; ANTIHYPERTENSION
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.07.023

A series of new angiotensin II (Ang II) receptor 1 antagonists were designed, synthesized and evaluated. All compounds showed nanomolar affinities for the angiotensin II type 1 receptor in radioligand binding assays and could reduce blood pressure significantly in spontaneously hypertensive rats(SHRs). From which, compound 2b displayed higher affinity binding to angiotensin II type 1 receptor at the same order of magnitude to irbesartan with an IC50 value of 1.26 ± 0.08 nM in radioligand binding assays. 2b showed an efficient and long-lasting effect in reducing blood pressure, the maximal reducing responses were 40.62 ± 4.08 mmHg of MBP at 15 mg/kg and 28.39 ± 2.09 mmHg at 10 mg/kg in SHRs, 39.56 ± 4.83 mmHg at 15 mg/kg and 29.05 ± 2.20 mmHg at 10 mg/kg in RHRs, the significant antihypertensive effect lasted beyond 12 h both in SHRs and in RHRs. In the single-dose pharmacokinetic experiments, compound 2b could be absorbed efficiently and metabolized smoothly in Wistar rats after oral administration. The values of Cmax, Tmax, AUC0–72 and MRT0–72 were 885.61 ± 432.7 ng/mL, 5.67 ± 1.51 h, 6110.28 ± 7398.33 ng/mL h and 7.87 ± 2.30 h at 10 mg/kg, 2945.55 ± 1543.67 ng/mL, 4.33 ± 0.82 h, 26473.62 ± 12217.16 ng/mL h and 10.24 ± 6.94 h at 15 mg/kg, 5759.03 ± 1331.75 ng/mL, 5 ± 1.10 h, 89488.44 ± 18413.15 ng/mL·h and 12.89 ± 2.0 h at 30 mg/kg respectively. The T1/2 values of the three groups were similar, about 9–10 h. Compound 2b was distributed into tissues rapidly and extensively after oral administration. The level of it was the highest in the liver, followed by in spleen, kidney, and the lowest in brain. The acute toxicity assays of 2b proved its low acute toxicity with an LD50 value of 1551.71 mg/kg, and no toxicity reaction appeared at dose of 1200.00 mg/kg. These encouraging results make compound 2b an effective, long-lasting and safe anti-hypertensive drug candidate and worthy of further investigation. [Display omitted] •A series of novel angiotensin II receptor 1 antagonists were designed, synthesized and evaluated.•Compound 2b was found to be more effective in reducing blood pressure than irbesartan in vivo.•Compound 2b could be absorbed efficiently and metabolized smoothly in Wistar rats after oral administration.•Compound 2b was safe with low acute toxicity.•compound 2b has the potential to be developed as an effective anti-hypertension drug candidate.