Structural modifications of CGS 26303, a non-peptidic α-aminophosphonate dual ECE/NEP inhibitor lead, were performed to maximize inhibition of recombinant human ECE-1, while maintaining strong NEP ...inhibition. Specifically, substitution of the α-aminophosphonate moiety with aryl ethyl side-chains led to the discovery of a new class of potent, non-peptidic, dual inhibitors, such as CGS 31447, which blocked ECE-1 and NEP activities with IC
50's of 17 and 5 nM, respectively.
Structural modifications of CGS 26303, a non-peptidic α-aminophosphonate dual ECE/NEP inhibitor lead, were performed to maximize inhibition of recombinant human ECE-1, while maintaining strong NEP inhibition. Specifically, substitution of the α-aminophosphonate moiety with aryl ethyl side-chains led to the discovery of a new class of potent, non-peptidic, dual inhibitors, such as CGS 31447, which blocked ECE-1 and NEP activities with IC
50's of 17 and 5 nM, respectively.
The synthesis of three series of dicarboxylic acid dipeptide neutral endopeptidase 24.11 (NEP) inhibitors is described. In particular, the amino butyramide 21a exhibited potent NEP inhibitory ...activity (IC50 = 5.0 nM) in vitro and in vivo. Blood levels of 21a were determined using an ex vivo method by measuring plasma inhibitory activity in conscious rats, mongrel dogs, and cynomolgus monkeys. Free drug concentrations were 10-1500 times greater than the inhibitory constant for NEP over the course of a 6 h experiment. A good correlation of free drug concentrations was obtained when comparing values determined by the ex vivo analysis to those calculated from direct HPLC measurements. Plasma atrial natriuretic factor (exogenous) levels were elevated in rats and dogs after oral administration of 19a. Urinary volume and urinary sodium excretion were also potentiated in anesthetized dogs treated with 21a.
A variety of compounds were prepared to determine whether dual angiotensin converting enzyme (ACE)/thromboxane synthase (TxS) inhibition could be obtained in the same molecule. These compounds would ...be used to explore the concept that a dual inhibitor would have superior antihypertensive activity in the spontaneous hypertensive rat compared to an ACE inhibitor. Potent in vitro dual ACE and TxS inhibition was obtained in the same molecule with five series of compounds. Potent blood pressure lowering in the SHR was observed after oral administration of 8b and 11. However, a correlation between blood pressure lowering and the A1 pressor response inhibition was not observed. The blood pressure-lowering actions of enalapril were significantly potentiated by concurrent administration of 3, a thromboxane synthase inhibitor. Analysis of the area under the curve for 24 h showed nearly a doubling of the blood pressure-lowering effect.
The synthesis of two new series of dicarboxylic acid dipeptides and two sulfhydryl-containing inhibitors are described. The in vitro enkephalinase inhibition data and some in vivo analgesic data are ...presented for these compounds. For the dibenzylglutaric acid series structure-activity relationships and in vivo analgesic activity are discussed. The reverse amides, i.e., 4-amino-2,4-dibenzylbutyric acid derivatives, are also discussed. Two sulfhydryl-containing inhibitors showed good in vivo potency in the mouse jump-latency hot-plate test after peripheral administration at moderate low doses.
The preparation of two series of N-carbobenzoxy-gamma-D-glutamyl secondary 2S amino acids and (N-substituted gamma-D-glutamyl)indoline-2(S)-carboxylic acid dipeptides is described. In vitro ...inhibition of angiotensin converting enzyme (ACE) is reported for each compound, and the structure-activity relationship is discussed. Oral and iv inhibition of AI pressor response in vivo of selected compounds in Table II is also discussed. The most potent compounds in vitro, 3 and 6a, had an ACE IC50 of 7 and 2.7 X 10(-9) M, respectively.
