Synthesis and biological activity of pentapeptide analogs of the potent angiotensin converting enzyme inhibitor 5(S)-benzamido-4-oxo-6-phenylhexanoyl-L-proline

Abstract

Two pentapeptide analogs (14 [5(S)-[[N2(cyclodbutylcarbonyl)-L-lysyl]amino]-4-oxo-6-phenylhexanoyl-L-proline]and 15 [5(S)-[[N2-(cyclobutylcarbonyl)-L-lysyl]amino-2-methyl-4-oxo-6-phenylhexanoyl-L-proline]) of the ketomethylene-containing angiotensin converting enzyme (ACE) inhibitor 5(S)-benzamido-4-oxo-6-phenylhexanoyl-L-proline (1) were synthesized and evaluated as ACE [angiotensin converting enzyme] inhibitors and antihypertensive agents. Compounds 14 and 15 were very potent ACE inhibitors with I50 values of 7.0 and 3.0 nM, respectively, compared to an I50 [median inhibitory concentration] value of 70 nM for 1. Neither 14 nor 15 showed significant blood pressure lowering activity in renal hypertensive rats. Investigations conducted on a tritiated analog of 14 showed that 70% of an oral dose of this compound is absorbed but is rapidly excreted from the blood with a half life of 24 min. TLC of bile and urine contents in rats given tritiated 14 orally showed that it is excreted in > 90% unchanged form. This implies that a ketomethylene linkage can stabilize peptide amide linkages adjacent to it to peptidase degradation.