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

Abstract

In recent years there has emerged a number of agents that represent a new class of drugs called hybrid drugs, which combine in one molecule two distinct pharmacological activities (3 1). The antihypertensive agents, labetalol, which combines a-and 0-adrenoceptor blocking properties (7), and carvedilol, which combines vasodilator and P-adrenoceptor blocking properties ( 18, 4 I), are examples of this class of drug. BW A385C is a chemically novel antihypertensive agent that was designed to incorporate in a single molecule both angotensin-converting enzyme (ACE) inhibition and P-adrenoceptor blocking properties.In this article, we would like to review the preclinical pharmacology of this novel dual active agent and discuss its potential clinical utility. Fig. 1). BW A385C arose from a programme of research with the objective of developing a novel hybrid drug incorporating both ACE inhibitory and 0-adrenoceptor blocking properties. There is an extensive body of knowledge delineating structure-activity relationships of both P-adrenoceptor bloclung agents and ACE inhibitors (33,40). Both classes of agents have broad overlapping structural requirements for activity, each being able to accept a range of aromatic systems to provide highly active compounds. When we attempted to hybridise P-adrenoceptor blocking agents based on a benzene (atenolol-like) or naphthalene (propranolol-like) nucleus with an ACE inhibitor of the enalapril type, the resultant compounds failed to exhibit dual activity (2). However, we discovered that when the P-adrenoceptor blocking agent, pindolol and an ACE inhibitor of the enalapril type were used as templates for 84 CHEMISTRY The chemical structure of BW A385C is N-[(S)-l-carboxy-5-(4-[(S)-2-hydroxy-3-

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

“…Both classes of agents have broad overlapping structural requirements for activity, each being able to accept a range of aromatic systems to provide highly active compounds. However, when we attempted to hybridise P-adrenoceptor blocking agents based on a benzene (atenolol like) or naphthalene (propranolol like) nucleus with an ACE inhibitor of the enalapril type the resultant compounds failed to exhibit dual activity (Allan et al, 1986a). However, we discovered that when the P-adrenoceptor blocking agent, pindolol and an ACE inhibitor of the enalapril type were used as templates for chemical hybridisation, the resultant chemical hybrid had dual activity (Allan et al, 1986b (Buhler et al, 1972;Case et al, 1978) it is quite clear that P-adrenoceptor blocking agents can exert hypotensive actions independent of this system e.g.…”