In vivo pharmacology of dual neutral endopeptidase/angiotensin-converting enzyme inhibitors. 1996

A A Seymour, and M M Asaad, and B E Abboa-Offei, and P L Smith, and W L Rogers, and C R Dorso
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.

The natriuretic and depressor responses to novel dual inhibitors of neutral endopeptidase (NEP) EC 3.4.24.11 and angiotensin-converting enzyme (ACE) were used to assess their activity in conscious cynomolgus monkeys. A survey of mercaptopropanoyl inhibitors revealed that compounds containing alanylproline or certain surrogates reduced blood pressure and increased sodium excretion, indicating a desirable profile of in vivo activity. Additional compound evaluation required specific in vivo assays for NEP and ACE inhibition. Accordingly, the potency of novel inhibitors against NEP and ACE were determined in conscious monkeys by the potentiation of the natriuretic activity of exogenous human atrial natriuretic peptide and inhibition of the pressor response to angiotensin I, respectively. This strategy led to the discovery that optimal in vivo activity was achieved when the mercaptopropanoyl group was replaced with mercaptoacetyl and the C-terminal alanylproline was replaced with conformationally constrained dipeptidomimetics. This work culminated in the identification of BMS-182657 as a prototypic dual NEP/ACE inhibitor with a highly desirable profile of in vivo pharmacology.

UI MeSH Term Description Entries
D007668 Kidney Body organ that filters blood for the secretion of URINE and that regulates ion concentrations. Kidneys
D008252 Macaca fascicularis A species of the genus MACACA which typically lives near the coast in tidal creeks and mangrove swamps primarily on the islands of the Malay peninsula. Burmese Long-Tailed Macaque,Crab-Eating Monkey,Cynomolgus Monkey,M. f. aurea,M. fascicularis,Macaca fascicularis aurea,Monkey, Crab-Eating,Monkey, Cynomolgus,Crab-Eating Macaque,Burmese Long Tailed Macaque,Crab Eating Macaque,Crab Eating Monkey,Crab-Eating Macaques,Crab-Eating Monkeys,Cynomolgus Monkeys,Long-Tailed Macaque, Burmese,Macaque, Burmese Long-Tailed,Macaque, Crab-Eating,Monkey, Crab Eating
D009320 Atrial Natriuretic Factor A potent natriuretic and vasodilatory peptide or mixture of different-sized low molecular weight PEPTIDES derived from a common precursor and secreted mainly by the HEART ATRIUM. All these peptides share a sequence of about 20 AMINO ACIDS. ANF,ANP,Atrial Natriuretic Peptide,Atrial Natriuretic Peptides,Atriopeptins,Auriculin,Natriuretic Peptides, Atrial,ANF (1-126),ANF (1-28),ANF (99-126),ANF Precursors,ANP (1-126),ANP (1-28),ANP Prohormone (99-126),ANP-(99-126),Atrial Natriuretic Factor (1-126),Atrial Natriuretic Factor (1-28),Atrial Natriuretic Factor (99-126),Atrial Natriuretic Factor Precursors,Atrial Natriuretic Factor Prohormone,Atrial Natriuretic Peptide (1-126),Atrial Pronatriodilatin,Atriopeptigen,Atriopeptin (1-28),Atriopeptin (99-126),Atriopeptin 126,Atriopeptin Prohormone (1-126),Cardiodilatin (99-126),Cardiodilatin Precursor,Cardionatrin I,Cardionatrin IV,Prepro-ANP,Prepro-CDD-ANF,Prepro-Cardiodilatin-Atrial Natriuretic Factor,Pro-ANF,ProANF,Proatrial Natriuretic Factor,Pronatriodilatin,alpha ANP,alpha-ANP Dimer,alpha-Atrial Natriuretic Peptide,beta-ANP,beta-Atrial Natriuretic Peptide,gamma ANP (99-126),gamma-Atrial Natriuretic Peptide,Natriuretic Peptide, Atrial,Peptide, Atrial Natriuretic,Peptides, Atrial Natriuretic,Prepro ANP,Prepro CDD ANF,Prepro Cardiodilatin Atrial Natriuretic Factor,Pro ANF,alpha ANP Dimer,alpha Atrial Natriuretic Peptide,beta ANP,beta Atrial Natriuretic Peptide,gamma Atrial Natriuretic Peptide
D010446 Peptide Fragments Partial proteins formed by partial hydrolysis of complete proteins or generated through PROTEIN ENGINEERING techniques. Peptide Fragment,Fragment, Peptide,Fragments, Peptide
D011480 Protease Inhibitors Compounds which inhibit or antagonize biosynthesis or actions of proteases (ENDOPEPTIDASES). Antiprotease,Endopeptidase Inhibitor,Endopeptidase Inhibitors,Peptidase Inhibitor,Peptidase Inhibitors,Peptide Hydrolase Inhibitor,Peptide Hydrolase Inhibitors,Peptide Peptidohydrolase Inhibitor,Peptide Peptidohydrolase Inhibitors,Protease Antagonist,Protease Antagonists,Antiproteases,Protease Inhibitor,Antagonist, Protease,Antagonists, Protease,Hydrolase Inhibitor, Peptide,Hydrolase Inhibitors, Peptide,Inhibitor, Endopeptidase,Inhibitor, Peptidase,Inhibitor, Peptide Hydrolase,Inhibitor, Peptide Peptidohydrolase,Inhibitor, Protease,Inhibitors, Endopeptidase,Inhibitors, Peptidase,Inhibitors, Peptide Hydrolase,Inhibitors, Peptide Peptidohydrolase,Inhibitors, Protease,Peptidohydrolase Inhibitor, Peptide,Peptidohydrolase Inhibitors, Peptide
D001794 Blood Pressure PRESSURE of the BLOOD on the ARTERIES and other BLOOD VESSELS. Systolic Pressure,Diastolic Pressure,Pulse Pressure,Pressure, Blood,Pressure, Diastolic,Pressure, Pulse,Pressure, Systolic,Pressures, Systolic
D004232 Diuretics Agents that promote the excretion of urine through their effects on kidney function. Diuretic,Diuretic Effect,Diuretic Effects,Effect, Diuretic,Effects, Diuretic
D005260 Female Females
D000803 Angiotensin I A decapeptide that is cleaved from precursor angiotensinogen by RENIN. Angiotensin I has limited biological activity. It is converted to angiotensin II, a potent vasoconstrictor, after the removal of two amino acids at the C-terminal by ANGIOTENSIN CONVERTING ENZYME.
D000806 Angiotensin-Converting Enzyme Inhibitors A class of drugs whose main indications are the treatment of hypertension and heart failure. They exert their hemodynamic effect mainly by inhibiting the renin-angiotensin system. They also modulate sympathetic nervous system activity and increase prostaglandin synthesis. They cause mainly vasodilation and mild natriuresis without affecting heart rate and contractility. ACE Inhibitor,ACE Inhibitors,Angiotensin Converting Enzyme Inhibitor,Angiotensin I-Converting Enzyme Inhibitor,Angiotensin-Converting Enzyme Inhibitor,Kininase II Inhibitor,Kininase II Inhibitors,Angiotensin I-Converting Enzyme Inhibitors,Angiotensin-Converting Enzyme Antagonists,Antagonists, Angiotensin-Converting Enzyme,Antagonists, Kininase II,Inhibitors, ACE,Inhibitors, Angiotensin-Converting Enzyme,Inhibitors, Kininase II,Kininase II Antagonists,Angiotensin Converting Enzyme Antagonists,Angiotensin Converting Enzyme Inhibitors,Angiotensin I Converting Enzyme Inhibitor,Angiotensin I Converting Enzyme Inhibitors,Antagonists, Angiotensin Converting Enzyme,Enzyme Antagonists, Angiotensin-Converting,Enzyme Inhibitor, Angiotensin-Converting,Enzyme Inhibitors, Angiotensin-Converting,II Inhibitor, Kininase,Inhibitor, ACE,Inhibitor, Angiotensin-Converting Enzyme,Inhibitor, Kininase II,Inhibitors, Angiotensin Converting Enzyme

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