Diphenylpropionic Acids as New AT₁ Selective Angiotensin II Antagonists

Abstract

The synthesis and pharmacological evaluation of a new series of potent AT1 selective diphenylpropionic acid nonpeptide angiotensin II receptor antagonists are reported. The new compounds were evaluated for in vitro AT1 (rat liver) and AT2 (rat adrenal) binding affinity as well as for in vivo inhibition of angiotensin II-induced increase in mean arterial blood pressure in pithed rats. Unsaturation of the diphenylpropionic acids as well as substitution or replacement by alkyl groups of the pendant phenyl ring resulted in a decrease of potency. On the other hand, the presence of small alkyl groups in the alpha-position to the carboxylic acid was important for activity, with one of the resultant diastereoisomers (R*,R*) being ca. 10-fold more active than the other (R*,S*). Oral evaluation of the most active compounds in a furosemide-treated sodium-depleted rat model showed that compound 36g (UR-7198) reduced blood pressure dose dependently. This compound showed in vitro and iv potencies similar to that of the reference compound losartan but faster onset of action and somewhat greater oral activity, presumably due to its improved bioavailability.

Effects of Ionic Liquids on Pd‐Catalysed Carbon–Carbon Bond Formation

“…[36][37][38][39] As some β,β-diaryl acrylates are useful intermediates for the synthesis of angiotensin II antagonist, [40] platelet activating factors antagonist, [41] and SRS-A antagonists (slow-reacting substance of anaphylaxis), [42] the development of an efficient process for the Heck arylation of β-substituted acrylates would be of significant utility. [36][37][38][39] As some β,β-diaryl acrylates are useful intermediates for the synthesis of angiotensin II antagonist, [40] platelet activating factors antagonist, [41] and SRS-A antagonists (slow-reacting substance of anaphylaxis), [42] the development of an efficient process for the Heck arylation of β-substituted acrylates would be of significant utility.…”

The Heck Coupling Reaction Using Aryl Vinyl Ketones: Synthesis of Flavonoids

“…[4] Additionally, some β,β-diarylacrylates are useful intermediates in the synthesis of angiotensin II antagonists, [5] platelet activating factor (PAF) antagonists, [6] and SRS-A (slow-reacting substance of anaphylaxis) antagonists. [7] The sequential treatment of ethyl acrylate with two different aryl halides allowed the stereospecific preparation of either (Z)-or (E)-β,β-diarylacrylates depending on which aryl derivative was introduced first.…”

Pd–benzothiazol-2-ylidene complex in ionic liquids: Efficient catalyst for carbon–carbon coupling reactions

“…As some b,b-diaryl acrylates are useful intermediates for the synthesis of the angiotensin II antagonist [32], the platelet activating factors antagonist [33], and the SRS-A antagonists (slow-reacting substance of anaphylaxis) [34], the development of an efficient process for the Heck arylation of b-substituted acrylates would be of significant utility. Usually, the arylation of b-substituted, a,b-unsaturated enoates requires harsh reaction conditions, cyclopalladated phosphanes [26,35] or palladium acetate as catalysts, sterically hindered tertiary amines as bases and quaternary ammonium salts as phase-transfer agents in DMF or DMA as solvents [23].…”