PMID: 7932534Sep 16, 1994Paper

Bromobenzofuran-based non-peptide antagonists of angiotensin II: GR138950, a potent antihypertensive agent with high oral bioavailability

Journal of Medicinal Chemistry
D B JuddT A Panchal

Abstract

We have identified GR138950, a potent antagonist of the angiotensin II receptor with high oral bioavailability, as our second drug candidate to GR117289. Using GR117289, a compound with moderate bioavailability (20%) in man as a lead, we pursued a strategy aimed at enhancing bioavailability. The strategy was based on SAR established around the diacid GR117289, and from this, it was proposed that a monoacid, in particular a trifluoromethanesulfonamide, should be better absorbed after oral administration and have enhanced oral bioavailability. This led to the identification of GR138950, a potent antihypertensive agent in the renal hypertensive rat, causing sustained falls in blood pressure after oral administration. Oral bioavailability of GR138950 in rats and dogs is high, confirming that GR138950 is well absorbed after oral administration. Moreover, the low plasma clearance and long plasma half-life suggest that this compound will be suitable for once a day administration. Furthermore, the preliminary data indicate that the high bioavailability of GR138950 seen in rats and dogs translates to man. These results demonstrate clearly that GR138950 has the potential to be a clinically effective antihypertensive agent. Further studie...Continue Reading

Citations

Apr 19, 1985·Biochimica Et Biophysica Acta·R B Guyer, R A Deering
Mar 12, 2011·The Journal of Organic Chemistry·Amandine CarrërEmmanuel Bertounesque
Feb 24, 2001·Journal of Receptor and Signal Transduction Research·M J Robertson
Jun 23, 2015·Chemistry : a European Journal·Amélie PialatMarc Taillefer
Apr 30, 2017·Chemical Science·Hannes P L GemoetsTimothy Noël
Aug 30, 2019·Chemical Communications : Chem Comm·Paridhi SaxenaManmohan Kapur
Oct 24, 2001·The Journal of Organic Chemistry·Alan R. KatritzkyJianqing Li
Nov 13, 2010·Bioorganic & Medicinal Chemistry·Prashant NaikMange Ram Yadav

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