Discovery and development of beta-blockers

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Discovery and development of beta-adrenergic receptor antagonists (beta-blockers)
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Figure 1: The chemical structure of dichloroisoprenaline (INN) or dichloroisoproterenol (USAN), abbreviated DCI — the first β-blocker to be developed.

sympathomimetic amines on bronchodilation, uterine relaxation and heart stimulation. Although DCI had no clinical utility, a change in the compound did provide a clinical candidate, pronethalol, which was introduced in 1962.[2]

Development

History

The β-blockers are an immensely important class of drugs due to their high

pharmacological actions.[3] In 1948, Raymond P. Ahlquist published a seminal paper concluding his findings, that there were two distinct receptors for catecholamine drugs, and they caused different responses in the heart muscle. He labeled them α-and β-adrenoceptors. These findings were soon to be a foundation for further research into drug development.[4]

In the early 1960s,

oxygen consumption by interfering with the effects of catecholamines.[4] In 1958, the pharmacological properties of dichloroisoproterenol (DCI) were described, a β-antagonist discovered a few years before by the Eli Lilly group.[2] It was the synthesis of DCI which established that β-receptors could be chemically blocked and thus its existence could be confirmed.[5] DCI had no clinical utility but a replacement of the 3,4-dichloro substituents, with a carbon bridge to form a naphtylethanolamine derivative, afforded a clinical candidate, pronethalol.[2]

In April 1963, toxicity tests for pronethalol showed results of thymic tumours in mice. Nevertheless, it was launched under the trade name Alderlin, as the first clinically useful β-blocker. The launch took place in November 1963 when many small-scale

cardiovascular diseases such as arrhythmia, hypertension and hypertrophic cardiomyopathy.[4][7]

The evolution of non-selective and selective β-blockers

Figure 2: The chemical structure of practolol.

By the time propranolol was launched, ICI was beginning to experience competition from other companies. This potential threat led to ongoing refinements in the pharmacologic structure of β-blockers and subsequent advances in drug delivery. ICI studied analogues further and in 1970 launched practolol (figure 4) under the trade name Eraldin. It was withdrawn from the market a few years later because of the severe side effects it caused, nevertheless it played a large role in the fundamental study of β-blockade and β-receptors.[4] The withdrawal of Eraldin gave ICI the nudge to launch another β-blocker,

best-selling heart drug.[4] ICI's β-blocker project was based on Ahlquist's dual receptor theory. The drugs that were the outcome of this project, from propranolol to atenolol, helped to establish the receptor theory among scientist and pharmaceutical companies.[4][6]

The progress in β-blocker development led to the introduction of drugs with variety of properties. β-blockers were developed having a relative

vasodilator activity (nebivolol). In addition, long-acting and ultra-short formulations of β-blockers were developed.[7] In 1988, Sir James Black was awarded the Nobel Prize in Medicine for his work on drug development.[3][4][6][7]

Examples of non-selective β-blockers
A beta-blocker
Labetalol
A beta-blocker
Pindolol
A beta-blocker
Propranolol
A beta-blocker
Timolol
A beta-blocker
Sotalol
Examples of selective β1-blockers
A beta-blocker
Atenolol
A beta-blocker
Acebutolol
A beta-blocker
Bisoprolol
A beta-blocker
Nebivolol
A beta-blocker
Metoprolol

Mechanism of action

Pharmacokinetics

The β-adrenergic receptor antagonists all have similar

racemate, except for timolol.[8]

Binding to β adrenergic receptors

Figure 3: β-blockers cause a competitive inhibition of the β-receptor, which counters the effects of catecholamines.[9]

Three different types of β-adrenergic receptors have been identified by molecular pharmacology.

lusitropic effects of β-blockers. This increases the re-uptake of calcium by the sarcoplasmic reticulum.[10]

β-blockers are

myocardial muscle fibers.[12]

Selectivity

β-blockers can be

venous embolic events.[14]

Synthesis

Figure 4: Mono-alkylation of catechol to give an ether.
Figure 5: Two paths of alkylation with epichlorohydrin (ECH).

Synthesis for a standard β-blocker begins with the mono-alkylation of catechol to give an ether (see figure 4).[15]

The fundamental step, and usually the last, in the synthesis of β-blockers consists of adding a propanolamine side chain. This can be done following two paths which both involve

isopropyl amine or tert-butylamine, and leads to the aryloxypropanolamine compound that consist of a secondary amine. This amine is typically known as the structural requirement for the β-adrenergic blocking activity.[15]

(S)-propranolol

Figure 6: Synthesis of (S)-propranolol from α-naphthol and 3-bromopropanol.

Propranolol exist in two different enantiomers, (S)-(−)- and (R)-(+)-enantiomers. The (S)-

L-proline catalyzed asymmetric α-aminoxylation and a reduction is made with NaBH4 in methanol. A diol is obtained by Pd/C-catalyzed hydrogenolysis. Finally the diol is converted to epoxide using the Mitsunobu reaction and stirred with isopropyl amine in CH2Cl2 to give (S)-propranolol.[16]

Structure-activity relationship (SAR)

Figure 7: The oxymethylene bridge of propranolol can be seen inside the green ring.

β-blockers' binding site to the receptor is the same as for

adrenaline. This binding is based on hydrogen bonds between the β-blocker and the receptor, and therefore not based on covalent bonds, which results in the reversibility of the binding.[18] A significant step in the development of β adrenergic antagonists was the discovery that an oxymethylene bridge (—OCH2—, figure 7) could be inserted into the arylethanolamine structure of pronethalol to produce propranolol. Propranolol is an aryloxypropanolamine, which are more potent β-blockers than arylethanolamines. Today, most of the β-blockers used clinically are aryloxypropanolamines. The length of the side chain is increased when an oxymethylene bridge is introduced. It has been shown that the side chains of aryloxypropanolamine can adopt a conformation that puts the hydroxyl and amine groups in more or less the same position as with beta blocker that do not have this group as a part of the side chain.[2]

After the release of propranolol, relative lipophilicity of β-blockers as a significant factor in their varied and complex pharmacology, became an important factor. It was suspected that propranolol's centrally induced side effects could be due to its high lipophilicity. Thus, it was focused on synthesizing analogues with hydrophilic moieties, favourably placed to see if the side effects would decrease. Selecting para-acylamino groups as the hydrophilic moiety, scientists synthesized a group of para-acylphenoxyethanol and propanolamines, and selected practolol for clinical trials. Practolol had one property not previously seen with β-blockers, it exhibited cardioselectivity (β1 selectivity). Studies from practolol showed that moving the acylamino group to meta or ortho positions, on the benzene ring, caused a loss of selectivity but not loss of the β-blockade itself. This illustrated the significance of para-substitution for β1 selectivity of β-blockers.[5]

Figure 8: Structural activity relationship for β-blockers.

Figure 8 shows the

structure-activity relationship (SAR) for β-blockers. For the function of a β-blocker it's essential for the compound to contain an aromatic ring and a β-ethanolamine. The aromatic ring can either be benzoheterocyclic (such as indole) or heterocyclic (such as thiadiazole). This is mandatory.[5][19]
The side chains can be variable:

  • The X part of the side chain can either be directly linked to the aromatic ring or linked through a —OCH2— group
  • When X is —CH2CH2—, —CH=CH—, —SCH2— or —NCH2—, there is little or no activity
  • The R1 group can only be a secondary substitution and branched is the optimal choice
  • Alkyl (—CH3) substituents on the α, β or γ carbon (if X = —OCH2—) lower beta blockade, especially at the α carbon

The general rule for aromatic substitution is: ortho > meta > para. This gives non-selective β-blockers. Large para-substituents usually decrease activity but large ortho-groups retain some activity. Polysubstitution on carbon 2 and 6 makes the compound inactive but when the substitution is on carbon 3 and 5 there's some activity. For the highest cardioselectivity, the substituents should be as following: para > meta > ortho. All the β-blockade is in one isomer, (S)-aryloxypropylamine and (R)-ethanolamine.[5]

Clinical use

Cardiovascular indications

For decades β-blockers have been used in

anti-arrhythmic effects and also anti-ischemic effects.[10] A β-blocker therapy is also useful in myocardial infarction, independent to heart failure. The therapy has been very helpful for high-risk patients.[22] Although beta-blockers effectively lower blood pressure, they are not recommended as a first-line agent in the treatment of hypertension, as thiazides diuretics, ACE inhibitors, and calcium channel blockers show greater benefit.[23] Therefore, β-blockers are usually used alongside other blood pressure medications such as calcium channel blockers.[24] They also have an effect on cardiomyopathy, postural orthostatic tachycardia syndrome and portal hypertension, to name a few.[25][26][27]

Other indications

There are few diseases, other than cardiovascular diseases, that β-blockers have a clinical effect on. These diseases are mentioned in the following sub-chapters. In addition, there are diseases which β-blockers have a clinical effect but are not the first choice of treatment. They won't be mentioned in the sub-chapters.

Essential tremor

When symptoms of the essential tremors are considerably high, non-selective β-blockers are an important treatment option and usually the first choice. Studies have shown that propranolol did reduce symptoms the most in that category. The β-blockers can be used alone or in a combination.[28]

Glaucoma

adjunctive therapy to achieve a target IOP lowering. One of the most used drug in adjunctive therapy is dorzolamide.[29]

Teratogenicity

Hypertension is reported to complicate one out of ten pregnancies, which makes it the most common medical disorder in pregnancy. It is important to have a correct diagnosis of hypertension during pregnancy, with the emphasis on differentiating pre-existing hypertension from pregnancy induced hypertension (gestational and the syndrome of pre-eclampsia). During pregnancy, the challenge is to determine when to use antihypertensive medications and which level of blood pressure to target.[30] A balance has to be found between the potential risk to the health of the baby related to drug-exposure and the risk to the mother and baby due to an untreated medical condition (severe hypertension).[31]

Antihypertensive drug use during pregnancy is relatively common and increasing.[32] Only a small proportion of available antihypertensive drugs have been tested in pregnant women, and many are contraindicated.[citation needed] It is important to make the exposure of medications to the baby as small as possible.[30] It is not clear if treating women who have mild or moderate hypertension during pregnancy with anti-hypertensive medication is beneficial.[33][31]

The most common

cleft lip and neural tube defects.[35] The U.S. Food and Drug Administration (FDA) categorises β-blockers into different pregnancy categories depending on the safety of the drugs and they range from category B to D, that is, no β-blockers is completely safe for using during pregnancy [36]

Categories of β-blockers according to the FDA
Non-selective FDA category β1-selective FDA category
Labetalol C Atenolol D
Pindolol B Acebutolol B
Propranolol C Bisoprolol C
Timolol C Nebivolol C
Sotalol B Metoprolol C

See also

References

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  3. ^ a b Frishman, W.H. (December 2008). "Fifty years of beta-blockers: a revolution in CV pharmacotherapy". Cardiologytoday. Retrieved 5 November 2013.
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  36. ^ "FDA Pregnancy Categories" (PDF). University of Washington. Archived from the original (PDF) on 14 December 2010. Retrieved 11 November 2013.
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