Gpcrtractability Current Therapeutics

These cell surface receptors have historically been attractive drug targets for pharmaceutical companies. More than 30% of all prescription drugs are directed at fewer than 50 known receptors.5,7,8 One feature of this receptor family that makes it a tractable drug target is the host of physiological functions including homeostatic mechanisms (cardiovascular, gastrointestinal, and metabolic processes), central nervous system function, and growth that are regulated through the activation of GPCRs by their endogenous ligands, providing a large number of potentially selective targets. Dysregulation of these pathways often leads to pathophysiological consequences that can be ameliorated by selective antagonists to reverse those disease states resulting from excessive stimulation of the GPCR involved. Conversely, selective agonists stimulate GPCR pathways that are hypofunctioning to reverse a disease process physiologically.

The role of GPCRs in a variety of disease states has also been shown through the discovery of naturally occurring mutant GPCRs in humans that contribute to pathologic conditions and via the use of transgenic animals in which genes for both liganded and orphan GPCRs are knocked in or knocked out to allow a better understanding of the in vivo phenotype of the GPCR.

Another key aspect of the tractability of GPCRs as drug targets is the ability to design small molecules with high degrees of potency and selectivity. This potency arises from the specificity in binding to domains in the receptor site. The selectivity arises from the diversity in the primary structures of binding sites in other GPCRs across families and isoforms and also in the selective localization of the targeted GPCR in tissues responsible for regulating the targeted physiological function. These features will be discussed in greater depth below, beginning with a brief overview of the current popularity of GPCRs as targets for drugs used in humans today.

Based simply on the sales successes of drugs targeting these receptors, GPCRs are attractive targets. In 2003, total sales for the top 200 prescription drugs were over $218 billion worldwide. Forty-seven of these drugs target GPCRs and comprise almost 23% of the sales at $47 billion.9 Table 3.1 depicts the 20 best-selling GPCR-targeted drugs of 2003 including salmeterol, an antiasthmatic p2-adrenergic agonist; olanzapine, an antipsychotic 5-HT2/dopamine receptor antagonist; and clopidrogel, an antithrombotic P2Y12-purinergic receptor antagonist, all with annual sales near $4 billion. Several GPCRs have multiple top-selling drugs targeted at them including H1-antihistamines (fexofenadine, cetirizine, and desloratadine) and antihypertensive angiotensin II receptor antagonists (losartan, valsartan, cardesartan, and irbesartan). This demonstrates the attractiveness of such targets to pharmaceutical companies.

Another way of determining the impact of GPCRs on therapeutics is to examine the total number of prescriptions issued for drugs targeting GPCRs since many of these drugs are now available as generic versions and, while highly prescribed, do not generate the same revenues as newly introduced drugs normally included in the top 200 in sales. In 2003, total U.S. prescriptions for the top 200 prescribed drugs numbered over 2.2 billion. Fifty-eight of the drugs target GPCRs and included 527 million prescriptions — almost 24% of the total number of prescriptions.10 Table 3.2 lists the top 15 GPCR targets for which drugs were prescribed in 2003. The

TABLE 3.1

Twenty Top-Selling Drugs Targeting GPCRs in 2003a

TABLE 3.1

Twenty Top-Selling Drugs Targeting GPCRs in 2003a

Sales

Trade Name

Brand Name

GPCR

Indication

($ millions)

Salmeterol

Advair/Seretide/Serevent

ß2-adrenergic

Asthma

4,351

Olanzapine

Zyprexa

5HT2 and Dopamine

Schizophrenia

4,277

Clopidrogel

Plavix

P2Y 12-purinergic

Thrombosis

3,966

Losartan

Cozaar/Hyzaar/Nu-Lotan

ATj-angiotensin II

Hypertension

2,939

Risperidone

Risperdal

Dopamine

Schizophrenia

2,512

Valsartan

Diovan/Co-Diovan

AT1-angiotensin II

Hypertension

2,425

Montelukast

Singulair

CysLT1-leukotriene

Asthma

2,009

Fexofenadine

Allegra/Telfast

H1-histamine

Rhinitis

1,964

Tamsulosin

Flomax/Harnal

ß1-adrenergic

BPH

1,916

Leuprolide

Leuplin/Lupron

GnRH

Prostate cancer

1,664

Fentanyl

Duragesic

Opioid

Pain

1,631

Cadesartan

Blopress/Atacand

AT1-angiotensin II

Hypertension

1,629

Irbesartan

Aprovel/Avapro/Avalide

AT1-angiotensin II

Hypertension

1,530

Quetiapine

Seroquel

5HT2 and dopamine

Schizophrenia

1,487

Cetirizine

Zyrtec

H1-histamine

Rhinitis

1,353

Metoprolol

Toprol-XL/Seloken

ß1-adrenergic

Hypertension

1,280

Sumatriptan

Imitrex/Imigran

5HT1

Migraine

1,246

Goserelin

Zoladex

GnRH

Prostate cancer

869

Octreotide

Sandostatin

Somatostatin

Acromegaly

695

Desloratadine

Clarinex

H1-histamine

Rhinitis

a Based on sales.

opioid receptor was the target most prescribed for (including those for non-GPCRs), with nearly 147 million prescriptions written for a variety of opioid analgesic agonists including hydrocodone, oxycodone, morphine, and codeine. Other highly prescribed drugs include antagonists for the pradrenergic receptor, agonists for the p2-adrenergic receptor, and H1 antihistamines.

The vast majority of drugs that target GPCRs are directed at the rhodopsin-like Family A GPCRs, as shown in Figure 3.1, Table 3.1, and Table 3.2. Even in Family A, most of the drugs are further directed at GPCRs that are activated by small-molecule biogenic amine neurotransmitters such as acetylcholine (muscarinic receptors), epinephrine and norepinephrine (adrenergic receptors), dopamine (dopa-minergic receptors), histamine (histaminergic receptors), and serotonin (serotonergic receptors). Many of these receptors have long histories of research dating back decades before their actual cloning and were well characterized in vitro and in vivo as playing roles in a variety of pathophysiological disease states. This basic pharmacological understanding of the receptor and its role in disease and the ability to more easily design small molecules to bind to these biogenic amine GPCRs probably contributed to the preponderance of drugs directed at these targets today.

Additional criteria that play a role in determining the success of a drug directed at a particular GPCR will be described below. Although many peptide-liganded

TABLE 3.2

Fifteen Top GPCR Targets in 2003a

TABLE 3.2

Fifteen Top GPCR Targets in 2003a

Prescripti

GPCR

Function

Indication

Trade Names

(million

Opioid

Agonist

Pain

Hydrocodone,

146.7

propoxyphene,

codeine, oxycodone

ßrAdrenergic

Antagonist

Hypertension,

Metoprolol, atenolol,

96.7

Glaucoma

propranolol

H1-Histamine

Antagonist

Rhinitis, Vertigo

Fexofenadine, cetirizine,

71.6

meclizine

ß2-Adrenergic

Agonist

Asthma

Albuterol, salmeterol

49.7

AT1-Angiotensin II

Antagonist

Hypertension

Valsartan, losartan

38.8

CysLT1-Leukotriene

Antagonist

Asthma

Montelukast

18.5

P2Y12-Purinergic

Antagonist

Thrombosis

Clopidrogel

15.2

H2-Histamine

Antagonist

Acid Reflux

Ranitidine

13.7

Muscarinic

Antagonist

Asthma, Over-active

Ipratropium, tolterodine

12.0

Acetylcholine

bladder

a1-Adrenergic

Antagonist

BPH

Tamsulosin, terazosin

10.9

Dopamine

Antagonist

Schizophrenia

Risperidone

8.1

a2-Adrenergic

Agonist

Hypertension

Clonidine

7.2

Prostanoid FP

Agonist

Glaucoma

Latanoprost

6.9

5HT2 and Dopamine

Antagonist

Schizophrenia

Quetiapine

6.1

5HT1

Agonist

Migraine

Sumatriptan

4.5

a Based on number of prescriptions.

a Based on number of prescriptions.

Family A GPCRs are known, far fewer drugs on the market target them. However, a number of opioid receptor analgesic agonists such as morphine, oxycodone, and hydrocodone, among others, have been developed as effective narcotic analgesics used for the treatment of pain. In addition, small molecule antagonists to the angiotensin II receptor have been successfully designed and are effective for treating hypertension. Thus, good precedents have been established for creating effective drugs directed at peptide-liganded GPCRs. Indeed, the CXCR4 and CCR5 chemokine receptors are attractive GPCR targets for the development of new antiviral drugs to combat AIDS. Both of these receptors are used by HIV strains as coreceptors for entry into host target immune cells. Peptidic antagonists intended to block HIV entry into these cells are currently under development.11 Two potentially attractive drug candidates include the orally bioavailable low molecular weight SCH-C CCR5 antagonist that exhibits potent antiviral activity and has been shown to decrease viral load in HIV-infected subjects and the AMD3100 CXCR4 antagonist that blocks CXCR4-dependent viral replication.11 Among Family B GPCRs, synthetic agonist analogs such as leuprolide and goserelin are used thera-peutically to activate the gonadotropin-stimulating hormone receptor for the treatment of prostatic cancer.

Naturally Cure Your Headaches

Naturally Cure Your Headaches

Are Headaches Taking Your Life Hostage and Preventing You From Living to Your Fullest Potential? Are you tired of being given the run around by doctors who tell you that your headaches or migraines are psychological or that they have no cause that can be treated? Are you sick of calling in sick because you woke up with a headache so bad that you can barely think or see straight?

Get My Free Ebook


Responses

Post a comment