MEDICINAL CHEMISTRY – DRIVING THERAPEUTIC DISCOVERY

 

Professor Craig Lindsley, co-Director and Director of Medicinal Chemistry of the Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University outlines how medicinal chemistry plays a role in drug discovery…

Medicinal chemistry is the application of synthetic organic chemistry to biological problems with the end goal of developing a novel small molecule therapeutic agent to treat an unmet medical need. Medicinal chemists are charged with understanding all aspects of drug discovery (chemistry, pharmacology, drug metabolism and in vivo behaviour), and utilising these diverse inputs to design molecules suitable for use in humans while also enabling intellectual property position, e.g., patent protection. Moreover, the chemistry (e.g., chemical matter) varies across programs, and the medicinal chemist must be an astute synthetic chemist with a broad repertoire of chemical knowledge to be successful. It is often unappreciated, but like medical doctors, most medicinal chemists spend more than 10 years in undergraduate, graduate and post-graduate education before landing their first pharmaceutical position.

While drug discovery is the very definition of ‘big team science’, medicinal chemists are perhaps the most well-rounded of all the scientists, following programs from conception to the clinic. Without question, medicinal chemistry is the major force driving therapeutic discovery and improving human health over the last 100 years – from antibiotics to chemotherapy to schizophrenia. Consider the past 25 years of medical advancement for which medicinal chemistry has led the charge. Medicinal chemists have developed revolutionary treatments for HIV/AIDs, rendering it a manageable disease from what was formerly a death sentence, fundamentally changed cardiovascular health (and CV-related deaths) with the statins (e.g., Lipitor), produced game-changing cancer therapies that can add more than 10 life-adjusted quality years, and in 2014, with the launch of Sovaldi, an HCV cure that eliminated the need for liver transplants.

Great strides have also been made in terms of brain disorders and therapeutics for the central nervous system (CNS). Here, medicinal chemists play dual roles, developing not only the small molecule drugs, but also diagnostic and imaging agents to enable personalised, effective treatments across diverse patient populations. New small molecule therapies are under clinical development for schizophrenia, Parkinson’s disease (PD), major depressive disorder (MDD) and Alzheimer’s disease (AD) that represent novel mechanisms of action with disease modifying potential and offer efficacy far beyond the standard of care. For schizophrenia, medicinal chemists rescued patients from asylums and electroshock therapy, with drugs that address the positive, negative and cognitive symptoms and enable them to integrate back into society. To this point, the top selling small molecule drug last year was Abilify, an antipsychotic with world-wide sales in excess of $9.2bn. In the case of PD, scientists have studied the brain circuit modified by invasive surgical procedure known as deep brain stimulation (DBS), identified molecular targets (proteins) that can be modulated to mimic DBS output, and then, medicinal chemists created small molecules to engage these targets and normalise these dysfunctional circuits. Three new drugs have launched in recent years for Multiple Sclerosis (MS), which have transformed how this neurodegenerative disease is managed, and medicinal chemists are now focused on neuroprotection/neuro-restoration strategies that will impact a broader array of CNS disorders. Here, in CNS drug discovery, medicinal chemists truly shine. Not only do they have to design and synthesise compounds to engage the desired target, but they must be orally bioavailable (e.g., a pill), cross the blood-brain barrier (evolutionarily designed to keep foreign chemicals out), and be safe to allow daily maintenance therapy for life. These are incredibly difficult requirements and challenging obstacles, but medicinal chemists surmount these issues, as they know patients are waiting, and driven to impact human health.

Despite these successes, medicinal chemists are under great employment pressure from the fiscal realities of outsourcing in developing nations, from downsizing/lay-offs due to mergers/acquisitions in the pharmaceutical/biotech industry, as well as pharmacoeconomics. Thus, the ranks have greatly dissipated, by approximately 70%, in the United States and Europe during the past 2 decades. These trends should alarm the public. When the next “HIV-like” epidemic emerges, we will have neither the needed number nor the diversity of medicinal chemists in place to effectively rally and combat such a scenario as we did in the 1990s, with disastrous results for society. Moreover, we should all consider Alzheimer’s disease (AD), forecasted to affect 1 in 5 over 65 by 2030, for which we have no cure, only palliative treatments. Scientists and medicinal chemists need to focus on AD as the drug discovery challenge of this generation to find disease-modifying treatments.

Rest assured, it is not all gloom and doom – medicinal chemists are actively and passionately working on the design and synthesis of new small molecules to address the unmet medical needs of the day, gradually replacing invasive surgical procedures and extended hospitalisations with simple pills or capsules one can take at home, with great overall savings and benefits for society. The next time you have an ailment that a physician can prescribe a drug to treat, as opposed to surgery, you have a dedicated medicinal chemist to thank.