ABSTRACT
1-(Substituted)benzyl-5-aminoimidazole-4-carboxamides are potent orally active inhibitors of Trypanosoma cruzi infections in mice. The most active compounds are the 1-(4-chlorobenzyl)- and 1-(3,4-dichlorobenzyl)-analogs (L-153,094 [2] and L-153,153 [4], resp.) which are approximately 7-fold more potent upon oral administration than nifurtimox (Lampit) in suppressing parasite levels in the blood of mice with acute Trypanosoma cruzi infections.
Subject(s)
Aminoimidazole Carboxamide/analogs & derivatives , Aminoimidazole Carboxamide/therapeutic use , Antiprotozoal Agents/therapeutic use , Chagas Disease/drug therapy , Aminoimidazole Carboxamide/chemical synthesis , Animals , Antiprotozoal Agents/chemical synthesis , Computer Simulation , Female , Mice , Mice, Inbred Strains , Models, Molecular , Molecular Conformation , Structure-Activity Relationship , Trypanosoma cruziABSTRACT
The synthesis and some of the spectral properties of N2-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl-L-proline (lisinopril, MK-521) are described. This compound inhibits angiotensin-converting enzyme with an IC50 of 1.2 X 10(-9) M.
Subject(s)
Dipeptides/chemical synthesis , Carbon Isotopes , Chemical Phenomena , Chemistry , Lisinopril , Magnetic Resonance SpectroscopyABSTRACT
Much current attention focuses on the renin-angiotensin system in relation to mechanisms controlling blood pressure and renal function. Recent demonstrations (ref. 1, ref. 2 and refs therein) that angiotensin-converting enzyme inhibitors show promising clinical antihypertensive properties have been of particular interest. We now report on the design of a novel series of substituted N-carboxymethyl-dipeptides which are active in inhibiting angiotensin-converting enzyme at nanomolar levels. We suggest that these compounds are transition-state inhibitors and that extensions of this design to other metalloendopeptidases merit further study.
