Abstract
A potent macrocyclic inhibitor of neutral endopeptidase (NEP) 24.11 was designed using a computer model of the active site of thermolysin. This 10-membered ring lactam represents a general mimic for any hydrophobic dipeptide in which the two amino acid side chains bind to an enzyme in a contiguous orientation. The parent 10-membered ring lactam was synthesized and exhibited excellent potency as an NEP 24.11 inhibitor (IC50 = 3 nM). In order to improve oral bioavailability, various functionality was attached to the macrocycle. These modifications lead to CGS 25155, an orally active NEP 24.11 inhibitor that slows down the degradation of the cardiac hormone atrial natriuretic factor, producing a lowering of blood pressure in the DOCA-salt rat model of hypertension.
MeSH terms
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Administration, Oral
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Amino Acid Sequence
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Animals
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Antihypertensive Agents / chemical synthesis*
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Antihypertensive Agents / pharmacokinetics
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Antihypertensive Agents / therapeutic use
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Atrial Natriuretic Factor / blood
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Binding Sites
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Biological Availability
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Computer Simulation
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Crystallography, X-Ray
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Drug Design*
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Hydroxyproline / analogs & derivatives*
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Hydroxyproline / chemical synthesis
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Hydroxyproline / pharmacokinetics
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Hydroxyproline / therapeutic use
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Hypertension / blood
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Hypertension / chemically induced
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Hypertension / drug therapy
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Models, Molecular
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Molecular Sequence Data
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Molecular Structure
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Neprilysin / antagonists & inhibitors*
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Neprilysin / metabolism
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Peptides, Cyclic / chemical synthesis*
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Peptides, Cyclic / pharmacokinetics
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Peptides, Cyclic / therapeutic use
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Rats
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Thermolysin / chemistry
Substances
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Antihypertensive Agents
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Peptides, Cyclic
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CGS 25155
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Atrial Natriuretic Factor
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Neprilysin
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Thermolysin
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Hydroxyproline