Pharmaceutical “Gold” from Neurostabilizing Agents: Topiramate and Successor Molecules

Abstract

Like the alchemists of a bygone era, who sought to convert base metals into gold, the medicinal chemists of the 20th century had a comparable aspiration. However, their quest was the conversion of basic chemical elements, such as carbon, hydrogen, nitrogen, oxygen, and sulfur, into the modern-day equivalent of gold: life-saving, life-preserving, life-enhancing drugs. Walking in the footsteps of Paul Ehrlich and other drug discovery pioneers, these latter-day “alchemists” applied their scientific expertise, intellect, and intuition to the invention of magnificent new medicines. Indeed, contemporary medical practice, and the patients that it serves, have benefited enormously from the seminal pharmaceutical discoveries of this remarkable period. The second half of the 20th century, by virtue of key events, has been characterized in the annals of history as the “Space Age”, the “Computer Age”, and the “Atomic Age”. By the same token, the body of evidence also strongly indicates that this era deserves to be called the “Pharmaceutical Age”, despite the apparent absence of this term in the popular lexicon. In the post1950 world, drug discovery became an institution of the pharmaceutical age and medicinal chemistry became its touchstone. The maturation of medicinal chemistry as a scientific discipline was a critical driving force in the drug discovery process. And because of the rich cornucopia of new drug products, the pharmaceutical industry rocketed to a position of great status and wealth. The coveted icon ultimately became the “billion-dollar molecule”, which some have pinpointed as a prime source for today’s problems in the industry. But the difficulty in delivering new, impactful drugs in quantity has much to do with other issues, such as (1) the prior harvesting of the “low-hanging fruit”, (2) the lofty demands placed on new clinical candidates to meticulously de-risk them, and (3) the focus on chronic diseases with large, heterogeneous patient populations. Whether the sought-after drug would be blockbuster or not, wishful drug discoverers have never been completely clear on how to do the job right. Arguably, perhaps, there is no guaranteed way to successfully discover marketable drugs, and the rules, conditions, and environment keep on changing. Given the relentlessly shifting landscape over the lengthy time required to discover a drug and advance it to the market, the desirable end result is often derived more from good luck than from any other contributing factor. It is certainly unfortunate that many promising clinical compounds have dissolved into nothingness for reasons ranging from pharmacology to toxicology to economics to corporate psychology. For a medicinal chemist seeking to make the “big score”, the odds of success have become decidedly unfavorable. And those odds were fairly lean even in the golden years of drug discovery, in the late 20th century. TOPAMAX (topiramate) is marketed worldwide for the treatment of epilepsy and the prophylaxis of migraine headache. With annual sales of more than two billion dollars in 2006, † Contact information. Phone: 215-628-5530. Fax: 215-540-4612. E-mail: bmaryano@its.jnj.com. a Abbreviations: FBPase, fructose-1,6-bisphosphatase; GABA, γ-aminobutryric acid; IND, investigational new drug; MES, maximal electroshock seizure; OTC, over the counter.  Copyright 2009 by the American Chemical Society