A novel Sartan derivative with very low angiotensin II type 1 receptor affinity protects the kidney in type 2 diabetic rats.

Abstract

BACKGROUND:

Antihypertensive angiotensin II receptor blockers (ARBs) protect the kidney, at least in part, independently of blood pressure lowering. Still, the extent to which blood pressure lowering is related to renoprotection remains unclear.

METHODS AND RESULTS:

139 newly synthesized ARB-derivatives were assayed for inhibition of advanced glycation (AGEs). The 9 most powerful compounds were then tested for transition metal chelation, angiotensin II type 1 receptor (AT1R) affinity, and pharmacokinetic parameters. R-147176 was eventually selected as it strongly inhibits advanced glycation but is 6700 times less effective than olmesartan in AT1R binding. It is orally bioavailable and toxicologically safe. Despite a minimal blood pressure lowering effect, it provides significant renoprotection in 3 experimental rat models with renal injury, ie, obese, hypertensive, type 2 diabetic rats (SHR/NDmcr-cp), normotensive type 2 diabetic rats (Zucker diabetic fatty), and remnant kidney rats.

CONCLUSIONS:

R-147176 retains renal protective properties despite a minimal blood pressure-lowering effect. Clearly, the renal benefits of ARBs do not necessarily depend on blood pressure lowering and AT1R affinity, but rather on the inhibition of AGEs and oxidative stress inherent to their chemical structure. R-147176 opens new avenues in the treatment of cardiovascular and kidney diseases.

• Authors: Yuko Izuhara, Toshio Sada, Hiroaki Yanagisawa, Hiroyuki Koike, Shuichi Ohtomo, Takashi Dan, Sadayoshi Ito, Masaomi Nangaku, Charles van Ypersele de Strihou, Toshio Miyata
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 28 Issue 10 Pg. 1767-73 (Oct 2008) ISSN: 1524-4636 [Electronic] United States
• PMID: 18658044 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin II Type 1 Receptor Blockers
• Antihypertensive Agents
• Antioxidants
• Chelating Agents
• Glycation End Products, Advanced
• Imidazoles
• R 147176
• Receptor, Angiotensin, Type 1
• Thiazolidinediones

Topics

• Angiotensin II Type 1 Receptor Blockers (pharmacokinetics, pharmacology, toxicity)
• Animals
• Antihypertensive Agents (pharmacology)
• Antioxidants (pharmacology)
• Blood Pressure (drug effects)
• Cell Survival (drug effects)
• Chelating Agents (pharmacology)
• Diabetes Mellitus, Type 2 (complications, drug therapy, metabolism, physiopathology)
• Diabetic Nephropathies (etiology, metabolism, physiopathology, prevention & control)
• Disease Models, Animal
• Glycation End Products, Advanced (metabolism)
• HeLa Cells
• Humans
• Imidazoles (pharmacokinetics, pharmacology)
• Kidney (drug effects, metabolism, pathology)
• Male
• Nephrectomy
• Oxidative Stress (drug effects)
• Protein Binding
• Rats
• Rats, Inbred SHR
• Rats, Wistar
• Rats, Zucker
• Receptor, Angiotensin, Type 1 (metabolism)
• Thiazolidinediones (pharmacokinetics, pharmacology)
• Time Factors