Target Validation

Even if potent and selective chemical structures exist for a molecular target, the target is not validated for therapeutic intervention until efficacy can be demonstrated in clinical trials. Both the compound and the target are only fully validated for a disease when a drug is registered for the marketplace, which reflects the adequate safety or therapeutic index for a specified patient population by a specific route and frequency of dosing. For example, impairment of cholinergic pathways in the brain has long been believed to result in synaptic disruption and cognitive impairment leading to memory loss, also referred to as the "cholinergic hypothesis." Acetylcholinesterase inhibitors have been approved, such as tacrine (Cognex, Parke-Davis, Ann Arbor); donepezil hydrochloride (Aricept, Eisai/Tokyo and Pfizer/New York); rivastigmine tartrate (Exelon, Novartis Pharmaceuticals, Basel); and galantamine hydrobromide (Reminyl, developed by Johnson & Johnson/New Brunswick and Shire Pharmaceuticals/Wayne, manufactured and marketed by Janssen Pharmaceutica/Titusville), for delaying the progression of cognition or memory loss by allowing significant levels of the neurotransmitter acetylcholine to be sustained in the synapse, but direct cholinergic agonists or mimetics have not yet been approved. Several have been studied clinically; a few have shown efficacy that might validate the target, but none have yet shown a safe therapeutic index to warrant approval. Is it because the drug candidates discovered so far are inadequately selective for brain cholinergic receptors (such as the Ml muscarinic and a2^4 nicotinic receptor subtypes) and cause too many peripheral cholinergic effects? Antimuscarinic drugs have actually been shown to increase Alzheimer's pathology in Parkinson's disease.12 This is a working hypothesis, but until a more selective compound can be shown to be efficacious and garner approval, stimulation of postsynaptic cholinergic receptors by muscarinic agonists is not a validated therapeutic target.

Glutamate receptors have represented attractive drug discovery targets for two decades because glutamate is the major excitatory neurotransmitter in the brain. Antagonists of glutamate receptors, especially NMDA antagonists, have been studied to reduce conditions like schizophrenia, epilepsy, neuropathic pain, and anxiety, but side effects have halted the development of most of these compounds. Are the compounds not sufficiently selective between the different glutamate receptor subtypes? Do the compounds provoke other activities related to their structure? Are the compounds readily accessible to the critical brain sites? Are the NMDA receptors the critical ones related to these disease conditions? The recent approval of memantine (Namenda, Forest Pharmaceuticals, St. Louis; Axura, Merz+/Germany; and Ebixa, Lundbeck/Copenhagen) for severe cognitive impairment, but not for mild cognitive impairment, does not unequivocally validate the target because memantine is neither a potent nor a selective NMDA modulator, so we cannot conclude that NMDA antagonism is the mechanism underlying its efficacy.

Another problem in validating targets for behavioral disorders related to neurotransmit-ter abnormalities is the interplay between several neurotransmitter systems in specific brain regions. For example, in the hippocampus, limbic, and nigral-striatal areas, functions connected by serotonin, norepinephrine, and dopamine are interconnected so that blocking selected receptor subtypes or changing synaptic levels of certain neurotransmitters may affect other transmitters or receptors at the same time. Postsynaptic receptor antagonists may provoke similar behavioral effects as presynaptic agonists or reuptake inhibitors (such as selective serotonin reuptake inhibitors, SSRIs) because presynaptic terminals may be connected to postsynaptic receptors using different neurotransmitters. Furthermore, patients with the same affective disorder may have malfunctions involving different neurotransmitters and require different therapeutic intervention to change the symptoms. All patients with a similar symptom complex may not have the same molecular target malfunction or may not respond well to the same compound or mechanism.

Recently, several groups have clinically evaluated compounds designed to increase or decrease synaptic levels of multiple neurotransmitters concurrently, such as norepineph-rine plus dopamine or norepinephrine plus serotonin. The intent is to effectively treat a broader population with similar symptoms. Conversely, Merck and Pfizer's discontinuance of clinical trials of peptide Y antagonists for depression does not disprove the validation of that target until the results are better understood and can answer such questions as: Was efficacy inadequate for a potent and selective compound? Was selectivity of the compound for the target inadequate? Does the molecular target not relate directly to the disease or have too many disconnects in the pathway to the disease?

Validation of a molecular target for a particular disease can shorten the drug discovery process. Discovery groups seek different chemical structures with similar potency and selectivity for a validated target to obtain its own patent protection. They may seek compounds with better brain bioavailability (especially by oral administration), with less-rapid metabolism, or with additional disease claims based on the validated target and mechanism, but all of these drug discovery approaches are of lower risk because the target has been validated. When several drugs are approved in a class, later entries often capture larger market shares if they have fewer side effects or provide better patient compliance or are effective in a broader patient population. The first "blockbuster" in the class requires validation of the target and evidence of safety for the target over long-term dosing and high doses. Expansion of the target to multiple drugs happens quickly after target validation — such as beta blockers, angiotensin-converting enzyme (ACE) inhibitors, H2 antagonists, proton pump inhibitors, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), and SSRI antidepressants.

Until recently, there have been few targets resulting in blockbusters in CNS and neurologic diseases, primarily because of the lack of validated targets and the reluctance of psychiatrists to prescribe drugs over the long term. The benzodiazepine anxiolytics were the first major class, although their mechanism was not a clearly defined target, and their use decreased when addiction and abuse were associated with the drugs. SSRIs for depression have become the first major target-validated class with blockbuster commercial status because they are relatively safe, not abusable by outpatients, and effective over time without much tolerance build-up. The cholinesterase inhibitors for cognitive impairment have emerged as the next blockbuster class for neuropsychiatric disorders.

Free Yourself from Panic Attacks

Free Yourself from Panic Attacks

With all the stresses and strains of modern living, panic attacks are become a common problem for many people. Panic attacks occur when the pressure we are living under starts to creep up and overwhelm us. Often it's a result of running on the treadmill of life and forgetting to watch the signs and symptoms of the effects of excessive stress on our bodies. Thankfully panic attacks are very treatable. Often it is just a matter of learning to recognize the symptoms and learn simple but effective techniques that help you release yourself from the crippling effects a panic attack can bring.

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