ro-42-5892 and Heart-Failure

The renin-angiotensin system (RAS) functions as a primary regulator in the short-term and long-term control of blood pressure. Pharmacologic inhibition of the RAS with angiotensin-converting enzyme (ACE) inhibition is effective for treating systemic hypertension and congestive heart failure. As a more specific therapy, the development of renin inhibitors has evolved through various approaches: specific renin antibodies, peptides developed from prosegments of renin precursor, oligopeptides related to pepstatin a universal inhibitor of aspartyl proteinase enzyme, and analogs of angiotensinogen (the renin substrate). Angiotensinogen analogs are promising as therapeutic agents because of high potency, metabolic stability, and good oral bioavailability. Ongoing research is directed towards the application of renin inhibition, the treatment of various cardiovascular disorders, and as a biological probe for understanding the role of the RAS in control of blood pressure and blood volume.

Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Heart Failure; Humans; Hypertension; Imidazoles; Morpholines; Pharmacology, Clinical; Piperazines; Renin; Renin-Angiotensin System; Thiazoles

To review the chemistry, pharmacokinetics, and clinical trials of two new classes of antihypertensive drugs, angiotensin II-receptor antagonists and renin inhibitors.. Primary literature on angiotensin II-receptor antagonists and renin inhibitors was identified through a comprehensive medical literature search from 1961 through 1993. This search included journal articles, abstracts, and reports of both animal and human research published in the English language. Indexing terms included renin-angiotensin aldosterone system, renin inhibitors, angiotensin II antagonists, DuP 753, losartan, MK954, A-64662, and Ro 42-5892.. Emphasis was placed on clinical and pharmacokinetic studies in humans for drugs that are currently in Phase I-III research protocols in the US.. All available data from human studies were reviewed.. Angiotensin II-receptor antagonists and renin inhibitors may be effective antihypertensives with few adverse effects noted in the small studies completed. Their potential advantage over angiotensin-converting enzyme (ACE) inhibitors includes a possible smaller adverse effect profile. In the past, the clinical utility of angiotensin II-receptor antagonists and renin inhibitors has been limited because of poor oral bioavailability, although newer agents are more readily bioavailable.. Angiotensin II-receptor antagonists and renin inhibitors may be the next new classes of antihypertensives marketed. However, definitive conclusions about their roles in the management of hypertension are not possible until larger clinical trials assessing their efficacy and safety and comparing them with ACE inhibitors are completed.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Antihypertensive Agents; Biphenyl Compounds; Clinical Trials as Topic; Dipeptides; Heart Failure; Humans; Hypertension; Imidazoles; Losartan; Renin; Tetrazoles