Chapter 21 Case Study Answer

Conduct a thorough and mechanistic SAR analysis of the 3 therapeutic options in the case.

Structure 1 is an aryloxypropanolamine. This identifies it as a -adrenergic blocker. The

N-isopropyl group directs it toward the -receptors without any selectivity. 1 receptor

selectivity occurs with aryloxypropanolamines that have a para-substituted phenyl as the aryl

moiety. 1 receptor antagonists block the effects of epinephrine and norepinephrine on the heart

and are used as antianginal, antihypertensives, and antiarrythmic drugs. As an antiarrythmic,

structure 1 is a Class II antiarrythmic, primarily affecting the SA and AV nodes slowing phase 4

depolarization and slowing SA node firing and AV node conduction prolonging repolarization.

Structure 1 is metabolized by CYP450 isozymes 2D6 and 1A2 to hydroxylated and N-

dealkylated products respectively.

Structure 2 is an organic nitrate. Organic nitrates release NO which activates guanylate

cyclase causing an increase in cGMP. The cGMP activates kinases that phosphorylate myosin

light chain kinase, deactivating it and leading to vascular smooth muscle relaxation. The

generation of NO from organic nitrates is thought to occur through an intermediate nitrosothiol

formed from either cysteine or glutathione reaction. Organic nitrates are metabolized by

glutathione-nitrate reductase in the liver.

Structure 3 looks a lot like structure 1. As a matter of fact it is also an

aryloxypropanolamine and one would expect it to have -adrenergic receptor blocking activity.
In addition, structure 3 has a phenylpropanone moiety ortho to the oxypropanolamine on the aryl

ring. This structural combination confers predominant antiarrhythmic activity. Structure 3 is a

class 1C antiarrhythmic acting on ventricular tissue, blocking Na+ channels, slowing the rate of

Na+ dissociation, slowing phase 0 depolarization and slowing impulse conduction. Hepatic

metabolism is polymorphic and determined genetically. Ten percent of Caucasians have a

reduced capacity to hydroxylate it to form 5-hydroxypropafenone.

Apply the chemical understanding gained from the SAR analysis to this patient’s specific

needs to make a therapeutic recommendation.

Structure 1 is propranolol. It would be a good choice as the second drug to help protect

SB from a silent ischemic heart attack. However, it would be a poor choice in this case since -

receptor antagonists are contraindicated for diabetics.

Structure 2 is isosorbide mononitrate. It would be the drug of choice in this case since it

is a long-acting organic nitrate, can be used in the diabetic patient, and has a different mechanism

of action for treating silent ischemic heart disease than the calcium channel blocker nifedipine.

Structure 3 is propafenone and would be a very poor choice in this case. It is primarily

used to treat ventricular and supraventricular arrhythmias. It does not have very significant -

adrenergic blocking action but could still affect SB’s blood glucose levels.