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Development of selective non-peptide angiotensin II type 2 receptor agonists
Department of Medicinal Chemistry, BMC, Uppsala University, Uppsala, Sweden
* To whom correspondence should be addressed. E-mail: mathias.alterman{at}orgfarm.uu.se.
The development of the first drug-like selective angiotensin II type 2 (AT2) receptor agonist (22) derived from the non-selective angiotensin II type 1 (AT1) receptor/AT2 receptor agonist L-162,313 is presented. Compound 22 with a Ki value of 0.4 nM for the AT2 receptor and a Ki > 10 μM for the AT1 receptor induces outgrowth of neurite cells, stimulates p42/p44mapk, enhances in vivo duodenal alkaline secretion in Sprague- Dawley rats and lowers the mean arterial blood pressure in anaesthetised spontaneously hypertensive rats. Thus, the peptidomimetic 22 exerts a similar biological response as the endogenous peptide angiotensin II after selective activation of the AT2 receptor. In addition, Compound 22 has a bioavailability of 20–30% after oral administration and a half-life estimated to four hours in the rat. Compound 22 will therefore serve as a valuable research tool enabling studies of the function of the AT2 receptor in more detail.
First published on October 30, 2009 |
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