Benzofuran based non-peptide antagonists of angiotensin II related to GR117289: part IV; imidazopyridinylbenzofurans.

Peptides as Therapeutic Agents or Drug Leads for Autoimmune, Hormone Dependent and Cardiovascular Diseases

“…In the following years, DuPont engaged in extensive studies to develop an Ang II receptor blocker and came up with a very promising molecule, Losartan [130], which is now among the most popular therapeutic agents for hypertensive conditions. Following these investigations, more structural modifications of non-peptidic antagonists led to increasingly potent orally active "sartans" by the pharmaceutical industry [131][132][133][134][135][136][137][138] with varying bioavailability and half-life profile Fig. (8) [139].…”

Nonpeptide Angiotensin II Receptor Antagonists: The Next Generation in Antihypertensive Therapy

“…Following the strategy of preparing monoacidic compounds to enhance oral absorption led to the replacement of the imidazole ring with the 5,7-dimethylimidazopyridine employed in the Merck compound L-158,809. This resulted in a potent benzofuran (p K B = 9.3, rabbit aorta) with a duration of action of >50 h when dosed orally at 1 mg/kg in renal artery-ligated hypertensive rats . Oral bioavailability in rats was 70%, and plasma clearance was low.…”

“…Oral bioavailability in rats was 70%, and plasma clearance was low. Evaluation of the metabolites of this compound resulted in the preparation of the 5-hydroxymethyl derivative GR159763 (p K B = 8.6, rabbit aorta). , This compound when dosed at 1 mg/kg, po, to RHR showed a significant decrease in blood pressure which lasted for more than 24 h. HPLC analysis showed that GR159763 was not metabolized to the corresponding 5-carboxylic acid in contrast to losartan. Pharmacokinetic studies showed GR159763 to have excellent bioavailability in the rat and a low value for plasma clearance which is indicative of high metabolic stability …”

An update on non-peptide angiotensin receptor antagonists and related RAAS modulators

“…Zolasartan is a potent, selective antagonist possessing long-lasting antihypertensive effect . In saprisartan, the imidazole carboxylic acid of zolasartan is replaced by a neutral imidazole-5-carboxamide to enhance its oral bioavailability (Judd et al, 1994) and tetrazole is replaced with triflamide (Dowle et al, 1993). Saprisartan has high affinity for the AT 1 receptors, and better bioavailability than zolasartan in experimental animals and human beings (Judd et al, 1994;Hilditch et al, 1995).…”