Philippe R. Bovy

Specific inhibitors of endopeptidase 24.11 inhibit the metabolism of atrial natriuretic peptides in vitro and in vivo

Atrial natriuretic peptides (ANPs) are degraded rapidly by renal brush border membranes in vitro. Here, we report that thiorphan, a specific inhibitor of endopeptidase 24.11, afforded almost complete protection against inactivation of ANPs by a renal brush border membrane preparation. The diastereoisomers of [3-(N-hydroxy)carboxamido-2-benzylpropanoyl]-L-alanine (HCBA) are potent inhibitors of endopeptidase 24.11 and were also tested for their abilities to inhibit ANP-(103-126) degradation. The (S,S)-diastereoisomer was more effective than the (R,S)-diastereoisomer (kelatorphan), but both were less potent than thiorphan. To determine if endopeptidase inhibitors could decrease ANP metabolism in in vivo, thiorphan and (S,S)-HCBA were given to rats with or without a continuous infusion of ANP-(103-126). Both inhibitors induced rapid increases in plasma ANP concentration in rats administered exogenous ANP-(103-126), but had no effect on endogenous ANP levels. Thus, specific inhibitors of endopeptidase 24.11 decrease the degradation of ANPs in vitro, and are effective in reducing the metabolism of ANP-(103-126) in vivo.

Peptide mimetic compounds useful as platelet aggregation inhibitors

This invention relates to having the following formula ##STR1## or a pharmaceutically acceptable salt which are useful in the inhibition of platelet aggregation. This invention also relates to pharmaceutical compositions of such phenyl amidines derivatives.

Synthesis and aldose reductase inhibition activity of spiro-[9H-fluoren-9,4'-imidazolidine]-2,5'-dione derivatives

Abstract A series of substituted spiro-[9 H -fluoren-9,4′-imidazolidine]-2′,5′-diones was prepared by Bucherer—Berg condensation followed by various modifications of a carboxylic functional group. The compounds obtained were examined for their abilities to inhibit the enzyme aldose reductase both in vitro and in vivo . High potency in inhibiting the semi-purified calf lens enzyme in vitro was observed for several of the tested compounds. Two of the compounds have been found to be very effective in reducing sorbitol accumulation in the lenses and sciatic nerves of rats treated with streptozotocin. Substitution on positions 1 or 2 of the fluorene ring led to inactive compounds, whereas substitution on positions 3 or 4 enhanced inhibitory activity with respect to the unsubstituted spirofluorohydantoin 50 . These observations are discussed in light of the previously published structural requirements of the allosteric binding site of the enzyme aldose reductase.