ct-Mercaptoaeyl dipoptides were prepared and found to inhibit angiotensin converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP). Compounds with a proline as the C-terminal amino acid, and possessing the S-stereochemistry at the thiol bearing carbon were preferred for optimal ACE inhibition while, R-stereochemistry was preferred for optimal NEP inhibition.
Compounds containing alternative amino acid residues at the C-terminal position displayed optimal dual ACE/NEP inhibition when the stereochemistry was 'S' at this carbon atom.
Medication for the treatment of hypertension today consists largely of angiotensin converting enzyme (ACE) inhibitors and calcium channel blockers prescribed alone or in combination with a diuretic. 2 Undesired side effects such as elevation of plasma renin levels, hypokalemia and hyperglycemia, upon treatment with a diuretic, make it desirable to have improved adjunct therapies available. It has been observed in animals and humans that, inhibitors of neutral endopeptidase 24.11 (NEP) produce diuresis with selective natriuresis. 3 This observation has led to the idea of combined inhibition of ACE and NEP for the treatment of hypertension and congestive heart failure (CI-IF). 4 We disclose herein, our initial results in the search for compounds that inhibit both ACE and NEp.5
In search of new templates for the dual inhibition of ACE and NEP both of which are zinc metalloproteases, we decided to initiate our study using the ct-thiols, IR and IS, as lead compounds. An additional amino acid at the C-terminus was envisioned to increase hydrophilic and hydrophobic interactions between the inhibitor and the two enzymes leading to improved dual activity. A terminal proline residue is known to be ideal for optimal ACE inhibition. 6 Therefore, we synthesized 2-6 as some of our initial 0~-mercaptoacyl dipeptide dual inhibitor targets. Further structure activity relationship (SAR) studies were done using other amino acids at the Cterminal and central positions. A recent publication 5d describing the SAR of ~-mercaptoacyl dipeptide series of ACE/NEP inhibitors mentions the dual activity of two epimers of a close analog of 2S without describing the SAR. Herein, we describe the SAR of ¢x-mercaptoacyl series of dual ACE/NEP inhibitors.
Compounds 1-5 were synthesized by coupling racemic 2-mercaptoacetyl-3-phenylpropionic acid with either (S)-4-phenylphenylalanine in the case of IR and IS or the appropriate dipeptide (AAt-Pro-OMe) as shown in Scheme I. The resulting mixture of diastereomers were separated into the SS and RS diastereomers which were