Design, synthesis, and biological evaluation of the first selective nonpeptide AT2 receptor agonist

Yiqian Wan; Charlotta Wallinder; Bianca Plouffe; Hélène Beaudry; A K Mahalingam; Xiongyu Wu; Berndt Johansson; Mathias Holm; Milad Botoros; Anders Karlén; Anders Pettersson; Fred Nyberg; Lars Fändriks; Nicole Gallo-Payet; Anders Hallberg; Mathias Alterman

doi:10.1021/jm049715t

Design, synthesis, and biological evaluation of the first selective nonpeptide AT2 receptor agonist

J Med Chem. 2004 Nov 18;47(24):5995-6008. doi: 10.1021/jm049715t.

Authors

Yiqian Wan¹, Charlotta Wallinder, Bianca Plouffe, Hélène Beaudry, A K Mahalingam, Xiongyu Wu, Berndt Johansson, Mathias Holm, Milad Botoros, Anders Karlén, Anders Pettersson, Fred Nyberg, Lars Fändriks, Nicole Gallo-Payet, Anders Hallberg, Mathias Alterman

Affiliation

¹ Department of Medicinal Chemistry, BMC, Uppsala University, P.O. Box 574, SE-751 23 Uppsala, Sweden.

PMID: 15537354
DOI: 10.1021/jm049715t

Abstract

The first druglike selective angiotensin II AT(2) receptor agonist (21) with a K(i) value of 0.4 nM for the AT(2) receptor and a K(i) > 10 microM for the AT(1) receptor is reported. Compound 21, with a bioavailability of 20-30% after oral administration and a half-life estimated to 4 h in rat, induces outgrowth of neurite cells, stimulates p42/p44(mapk), enhances in vivo duodenal alkaline secretion in Sprague-Dawley rats, and lowers the mean arterial blood pressure in anesthetized, spontaneously hypertensive rats. Thus, the peptidomimetic 21 exerts a similar biological response as the endogenous peptide angiotensin II after selective activation of the AT(2) receptor. Compound 21, derived from the prototype nonselective AT(1)/AT(2) receptor agonist L-162,313 will serve as a valuable research tool, enabling studies of the function of the AT(2) receptor in more detail.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Antihypertensive Agents / chemical synthesis
Antihypertensive Agents / chemistry
Antihypertensive Agents / pharmacology
Bicarbonates / metabolism
Biological Availability
Cell Line
Drug Design
Enzyme Activation
Female
Half-Life
In Vitro Techniques
Intestinal Mucosa / metabolism
Liver / metabolism
Male
Mitogen-Activated Protein Kinases / metabolism
Molecular Mimicry
Neurites / drug effects
Neurites / physiology
Peptides / chemistry
Radioligand Assay
Rats
Rats, Inbred SHR
Rats, Sprague-Dawley
Receptor, Angiotensin, Type 2 / agonists*
Receptor, Angiotensin, Type 2 / metabolism
Sulfonamides / chemical synthesis*
Sulfonamides / chemistry
Sulfonamides / pharmacology
Swine
Thiophenes / chemical synthesis*
Thiophenes / chemistry
Thiophenes / pharmacology
Uterus / metabolism

Substances

Antihypertensive Agents
Bicarbonates
N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulfonamide
Peptides
Receptor, Angiotensin, Type 2
Sulfonamides
Thiophenes
Mitogen-Activated Protein Kinases