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

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 studies are in progress to evaluate GR138950 in the treatment of hypertension.
AuthorsD B Judd, M D Dowle, D Middlemiss, D I Scopes, B C Ross, T I Jack, M Pass, E Tranquillini, J E Hobson, T A Panchal
JournalJournal of medicinal chemistry (J Med Chem) Vol. 37 Issue 19 Pg. 3108-20 (Sep 16 1994) ISSN: 0022-2623 [Print] UNITED STATES
PMID7932534 (Publication Type: Journal Article)
Chemical References
  • Angiotensin Receptor Antagonists
  • Antihypertensive Agents
  • Benzofurans
  • Receptors, Angiotensin
  • saprisartan potassium
  • Administration, Oral
  • Amino Acid Sequence
  • Angiotensin Receptor Antagonists
  • Animals
  • Antihypertensive Agents (metabolism, pharmacokinetics, pharmacology)
  • Benzofurans (metabolism, pharmacokinetics, pharmacology)
  • Biological Availability
  • Disease Models, Animal
  • Dogs
  • Hypertension (drug therapy)
  • In Vitro Techniques
  • Kinetics
  • Molecular Sequence Data
  • Rabbits
  • Rats
  • Receptors, Angiotensin (metabolism)
  • Structure-Activity Relationship

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