BW A575C, a chemically novel agent with angiotensin converting enzyme inhibitor and β‐adrenoceptor‐blocking properties

Abstract

) is a chemically novel agent which exhibits in a single molecule both angiotensin converting enzyme (ACE) inhibition and P-adrenoceptor-blocking properties.2 BW A575C produced a competitive blockade of heart rate responses to isoprenaline in a guinea-pig right atrial preparation (pKB 7.18 ± 0.05, cf. pindolol 8.9 ± 0.7). BW A575C inhibited a partially purified preparation of ACE obtained from rabbit lung (IC50 10.7 + 2.1 nM, cf. enalaprilat, 4.4 ± 0.8 nM).3 Intravenous administration of BW A575C (1-100 tgkg-' min-')to the pithed rat inhibited in a dose-dependent fashion both angiotensin I-induced pressor responses and isoprenaline-induced tachycardia. Dose-ratios obtained from such studies demonstrated that, in this preparation, BW A575C was approximately 100 times more active as an ACE inhibitor than as a P-adrenoceptor blocking agent. 4 Intravenous administration of BW A575C (I mg kg-') to the conscious rat inhibited angiotensin Iinduced pressor responses, being approximately equipotent to enalapril and 10 times more potent than captopril. At the same dose, BW A575C had a similar duration of action as an ACE inhibitor to enalapril. 5 Intravenous administration of BW A575C (I mg kg-') to either conscious dogs or rats inhibited both angiotensin I-induced pressor responses and isoprenaline-induced heart rate responses. Doseratios obtained from such studies demonstrated that in these species, BW A575C was 2-10 times more active as an ACE inhibitor than as a P-adrenoceptor blocking agent.

Pharmacology of celiprolol

“…For example, carvedilol is a bioavailable alphaand beta-adrenoceptor blocking drug. BWA 575C [3,4] is a novel drug that combines the properties of angiotensin-converting enzyme inhibition with betaadrenoceptor blockade. Another approach has been to separate and examine the pharmacology of the individual stereoisomers of labetalol.…”

Pharmacology of antihypertensive agents with multiple actions

“…This combined profile could also be demonstrated in normotensive rats and dogs as well as in conscious, renovascular hypertensive dogs [9]. The compound appears to be stable in vivo, in that it does not break down into two separate metabolites, with each containing one of the two pharmacodynamic components [8,10].…”

Preclinical Pharmacology of a Novel Dual Acting Angiotensin Converting Enzyme Inhibitor with β‐Adrenoceptor Blocking Properties

“…Although the molecule contains four chiral centres, one in the side chain associated with 0adrenoceptor blocking properties and the remainder in the peptide structure associated with ACE inhibition, BW A385C is a single diastereoisomer (S,S,S,S). The pharmacological activity of the mixed isomeric form of this hybrid drug, BW A575C, has been previously described (5).…”

“…The efficacy of ACE inhibitors in animal models of renovascular hypertension with elevated plasma renin is more established (23). Previous studies have demonstrated that BW A575C (the mixed isomeric form of BW A385C) has a potent antihypertensive action in the conscious renovascular hypertensive dog (4). In these studies, renovascular hypertension was induced by left renal artery stenosis to reduce flow by approximately 70%.…”