The chemistry of enalapril.

Aa, Patchett

doi:10.1111/j.1365-2125.1984.tb02599.x

Cited by 42 publications

(34 citation statements)

References 12 publications

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“…In order to compensate for the lack of the mercapto zinc ligand, these workers found it necessary to add two more binding radicals, making seven binding sites in all, as in the drug enalaprilat (Figure 3). Enalapril is an esterified pro-drug that yields the free acid, enalaprilat, an active ACE inhibitor possessing an I50 for the enzyme of 0.001 FLM, as compared with 0.023 FLM for captopril and 330.0 FLM for succinylproline (Patchett, 1984). Having in this way established the obligatory binding sites for effective inhibition of ACE, one can see clear analogies with the 'lock and key' hypothesis that formed the basis for the original development of organomercurial diuretics (Weiner et al, 1962).…”

Section: Chemical Evolution Oface Inhibitorsmentioning

confidence: 99%

Evolution of diuretics and ACE inhibitors, their renal and antihypertensive actions‐parallels and contrasts.

Lant

1987

Brit J Clinical Pharma

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1 The emergence of diuretic drugs and angiotensin converting enzyme (ACE) inhibitors ranks amongst the major therapeutic advances of modern medicine. The discovery of these drug groups arose largely by chance, yet each has dramatically influenced the treatment of congestive cardiac failure and arterial hypertension. 2 The central role which diuretics have had in the management of both oedema and hypertension hinges on their ability to induce a net renal excretion of solute and water by selective interference with either active or passive ion transport processes in different segments of the nephron. Irrespective of sites of action, the continued antihypertensive action of diuretics is characterized by a reduction in plasma volume and extracellular fluid (ECF) volume that lasts for as long as the diuretic is given. The mechanism of this effect remains unclear but may involve autoregulatory reactions that leave cardiac output unaltered but maintain a sustained reduction in total peripheral resistance. 3 ACE inhibitors also lower blood pressure by decreasing total peripheral resistance, leaving cardiac output, plasma volume and ECF volume unchanged. The detailed way these haemodynamic changes are achieved remains unknown but inhibition of converting enzyme present not only in the kidney but also in many extrarenal tissue sites, appears important. In both hypertension and cardiac failure, however, the kidney acts as a key target organ for ACE inhibitors. The increased renal vascular resistance and inappropriate renal salt excretion are reversed with enhanced renal blood flow and saluresis. Both angiotensin II (All) and vasopressin-mediated contraction of glomerular mesangial cells is inhibited, making glomerular filtration more efficient. Reduced aldosterone secondary to blockade of AII formation contributes to saluresis whilst encouraging positive potassium balance. ACE inhibition also impairs breakdown of kinins which may contribute to intrarenal and peripheral vasodilation either on their own or via release of prostaglandins and other vasoactive substances.4 The hypotensive actions of diuretics are potentiated by ACE inhibition primarily through blockade of AII formation and prevention of secondary aldosteronism. In combination, these drugs permit low doses to be used because of their synergistic effects. 5 Caution has to be exercised whenever ACE inhibition is used, without and especially with diuretics, in the management of renovascular hypertension and other low-perfusion states. In these circumstances, AII plays an important autoregulatory role in preserving glomerular filtration through an increase in post-glomerular resistance. Suppression of angiotensin formation with an ACE inhibitor can cause a critical reduction in glomerular perfusion. On the other hand, with careful titration, the dual actions of low-dose loop diuretics and an ACE inhibitor may be highly efficacious in treating severe heart failure and totally prevent such serious metabolic sequelae as azotaemia and hyponatraemia. 6 Unlike the experien...

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Section: Chemical Evolution Oface Inhibitorsmentioning

confidence: 99%

Evolution of diuretics and ACE inhibitors, their renal and antihypertensive actions‐parallels and contrasts.

Lant

1987

Brit J Clinical Pharma

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“…In particular, the use of ester-containing prodrugs in vivo can bring about improved bioavailability; the removal of ester functionalities is accomplished through enzyme catalysis or spontaneous hydrolysis. An example of a successful pharmaceutical masked with an ester group is enalapril (4), the structure of which is shown in Figure 2 (8).…”

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Ester Bonds in Prodrugs

Lavis

2008

ACS Chem. Biol.

137

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“…À época de sua descoberta, o ácido enalaprílico (15) revelouse com excelente atividade anti-hipertensiva, particularmente como inibidor da enzima conversora de angiotensina 42 . Entretanto, a alta polaridade dos dois grupos carboxílicos resultou em baixa absorção oral (<10%) 43 , o que implicava em uso apenas por via injetável.…”

Section: O Desenvolvimento Dos Pró-fármacos Enalapril E Bambuterolunclassified

Importância do metabolismo no planejamento de fármacos

Pereira¹

2007

Quím. Nova

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Recebido em 11/7/05; aceito em 10/2/06; publicado na web em 30/8/06 THE IMPORTANCE OF METABOLISM IN DRUG DESIGN. It is widely recognized that pharmacokinetic optimization needs to be addressed early in drug discovery to reduce the high failure rate in bringing drugs to market. Poor absorption, too short duration of action due to high elimination rate, or the presence of active metabolites are examples of properties that can potentially lead to unsuccessful clinical programmes. Here I describe a brief overview of advantages and molecular strategies for improving metabolic and pharmacokinetic properties applied to the discovery of fluconazol, β-blockers, ritonavir and ezetimibe and to the development of the prodrugs enalapril and bambuterol.Keywords: drug metabolism; drug design; structure-metabolism relationship. INTRODUÇÃOA ação de um fármaco, quando administrado a humanos ou animais, pode ser dividida em três fases: fase farmacêutica, fase farmacocinética e fase farmacodinâmica 1 (Esquema 1). Na fase farmacêutica, ocorre a desintegração da forma de dosagem, seguida da dissolução da substância ativa. A fase farmacocinética abrange os processos de absorção, distribuição, metabolismo e excreção (ADME), ou seja, "o que o organismo faz com o fármaco". A fase farmacodinâmica está relacionada com a interação do fármaco com seu alvo (receptor, enzimas etc.) e a conseqüente produção do efeito terapêutico, e pode ser entendida como "o que o fármaco faz no organismo".Nota-se que a fase farmacocinética pode ter profundo impacto sobre o efeito farmacológico, uma vez que os processos de ADME determinam a concentração e o tempo despendido das moléculas do fármaco no seu local de ação 2 . Tradicionalmente, a pesquisa de fármacos concentra seus esforços iniciais na fase farmacodinâmica. Triagens preliminares usam modelos in vitro, tais como enzimas, receptores ou tecidos, para obter a relação entre os novos compostos e sua potência agonista ou antagonista. A partir destes estudos, triagens secundárias e terciárias freqüentemente são dirigidas à administração do composto a animais, por via oral ou intravenosa, com observação do efeito farmacológico 3 . Entretanto, muitos dos compostos que se mostram promissores nos testes in vitro não apresentam boa atividade em animais 4 . Esta falha de correlação, muitas vezes associada a problemas farmacocinéticos dos compostos, como baixa biodisponibilidade, duração de ação (muito curta ou muito longa), ou a presença de metabólitos ativos, pode levar a programas clíni-cos mal-sucedidos. Para ilustrar, Prentis e colaboradores 5 relata- No processo de descoberta de novos medicamentos, a previsão dos processos de ADME logo nos estágios iniciais da pesquisa é de extrema importância 6 . A otimização destas propriedades, através de modificações moleculares de compostos promissores, é essencial na seleção de compostos candidatos com maiores probabilidades de não serem abandonados, mais adiante, na fase clínica. O fracasso na fase clínica representa grandes perdas de tempo e dinheiro 7 . Dentre as e...

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The chemistry of enalapril.

Cited by 42 publications

References 12 publications

Evolution of diuretics and ACE inhibitors, their renal and antihypertensive actions‐parallels and contrasts.

Evolution of diuretics and ACE inhibitors, their renal and antihypertensive actions‐parallels and contrasts.

Ester Bonds in Prodrugs

Importância do metabolismo no planejamento de fármacos

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