title: Synthesis and biological evaluation of a new angiotensin II receptor antagonist.
abstract: The design, synthesis, in vitro and in vivo evaluation of (2 R,6 S)-4-({1-[2-(1 H-tetrazol-5-yl)phenyl]-1 H-indol-4-yl}methyl)-2,6-dimethylmorpholine, compound 1, as a novel angiotensin II receptor antagonist is outlined. Radioligand binding assays showed that 1 displayed a high affinity for the angiotensin II type 1receptor with IC50 value of 0.82 nM. It acted as a potent anti-hypertensive derivative (maximal reduction of mean arterial pressure of 47 mm Hg at 10 mg/kg po in spontaneously hypertensive rat producing a dose-dependent fall in blood pressure following oral administration lasting beyond 10 h. Acute toxicity tests measured the LD50 of 1 value as 2431.7 mg/kg, which is higher than Losartan (LD50=2248 mg/kg). In addition further testing showed that 1 also demonstrated efficient anti-proliferative activity in vitro and anti-prostate cancer activity in vivo were also found. Taken together this compound could be considered as an effective and durable anti-hypertension drug candidate with additional anti-prostate cancer activity. These encouraging results are deserved of further investigation towards its use for therapeutic benefit.
authors.affiliation: Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai, China.
authors.forename: H-l
authors.initials: HL
authors.lastname: Zheng
authors.affiliation: Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai, China.
authors.forename: W-b
authors.initials: WB
authors.lastname: Zhu
authors.affiliation: Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai, China.
authors.forename: D
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai, China.
authors.forename: Y-j
authors.initials: YJ
authors.lastname: Da
authors.affiliation: Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai, China.
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Yan
authors.affiliation: Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Bian
authors.affiliation: Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, Shanghai, China.
authors.forename: Z-l
authors.initials: ZL
authors.lastname: Chen
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy; D051381:Rats; D011918:Rats, Inbred SHR; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D000970:Antineoplastic Agents; D044140:Receptor, Angiotensin, Type 1; D019808:Losartan