CRE-10904

CRE 10904 [2-(p-fluorophenoxy), 1-(o-hydroxyphenyl)-ethane, the leading compound of a new family of loop diuretic and antihypertensive agents: 1-aryl, 2-aryloxy-ethanes] induced high-ceiling natriuretic action in dogs and rats, but was completely inactive in pigs. High-performance liquid chromatography determinations revealed that all CRE 10904 (p.o. or i.v. administered) was rapidly sulfo-conjugated in dogs and rats, and glucurono-conjugated in pigs. The (O-sulfonyl)-CRE10904 metabolite (or simply CRE 11296) rapidly appeared in plasma, reached a concentration peak at about 40 min and disappeared with a half-life time of about 3 hr. The urinary excretion of CRE 11296 was correlated with the natriuretic activity of CRE 10904. Moreover, CRE 11296 was a powerful natriuretic compound in rats and dogs and, even in pigs, i.v. CRE 11296 induced transient natriuresis (just before its rapid hydrolysis and glucurono-conjugation). Studies in human red blood cells revealed that: 1) CRE 11296 was a potent inhibitor of the [Na+,K+,Cl-]-cotransport system (IC50 of 1.5 +/- 0.3 x 10(-5) M; mean +/- S.E.M. of 5 experiments), slightly more powerful than furosemide (IC50 of 2 x 10(-5) M), 2) it was the only diuretic drug potently inhibiting the [K+,Cl-]-cotransport system (IC50 of 2.1 +/- 0.6 x 10(-5) M; N = 3) and the [Cl/HCO3-] exchanger (IC50 of 4.5 +/- 1.0 x 10(-5) M; N = 3) and 3) CRE 10904 and its glucuronide were much less potent Cl- transport inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)

CRE 10904 (2-OHC₆H₄CH₂CH₂OC₆H₄F-4, I), the leading compound of a new family of loop diuretic and antihypertensive agents: 1-aryl- 2-aryloxy-ethanes, induced high-ceiling natriuretic action in dogs and rats, but was completely inactive in pigs.HPLC determinations revealed that all I (oral or i.v. administered) was rapidly sulfo-conjugated in dogs and rats, and glucurono-conjugated in pigs.The (O-sulfonyl)-I metabolite [CRE 11296, (II)] rapidly appeared in plasma, reached a concentration peak at about 40 min and disappeared with a half-life time of about 3 h.The urinary excretion of II was correlated with the natriuretic activity of I.Moreover, II was a powerful natriuretic compound in rats and dogs and, even in pigs, i.v. II induced transient natriuresis (just before its rapid hydrolysis and glucurono-conjugation).Studies in human red blood cells revealed that: (a) II was a potent inhibitor of the [Na⁺,K⁺,Cl^-]-cotransport system (mean IC₅₀ = 1.5 × 10^-5M in 5 experiments), slightly more powerful than furosemide (IC₅₀ = 2 × 10^-5 M), (b) it was the only diuretic drug potently inhibiting the [K⁺,Cl^-]-cotransport system (IC₅₀ = 2.1 × 10^-5M; N = 3) and the [Cl/HCO₃^-] exchanger (IC₅₀ = 4.5 × 10^-5M; N = 3) and (c) I and its glucuronide (III) were much less potent Cl^- transport inhibitors.In conclusion, these results strongly support the following mechanism of action: (a) I undergoes rapid and complete in vivo sulfation, (b) the sulfate metabolite is secreted into the proximal tubule (by the weak-acid carrier) and (c) high concentrations of the compound reach the luminal border of Henle's loop, where the R-O-SO₃^- group inhibits the [Na⁺,K⁺,Cl^-]-cotransport system at the chloride-receptor site.