Editorial [Hot Topic:Successful Drug Discovery: Rules and Examples (Guest Editor: Dr. David C. Swinney)]

A fundamental issue plaguing drug discovery is the high failure rate. Funding of the failed research is a contributor to the high cost of medicines and consequently, the rising cost of health care. How can the failure rate of drug discovery be minimized and the success rate of drug discovery increased? This issue of Current Topics in Medicinal Chemistry takes aim at learning what it takes for success from successful drug discovery. Three case studies and a review article provide insights into the process of successful drug discovery. What factors are important for drug discovery success? Two eminent drug discovers, Dr. Paul Janssen and Sir James Black, both found that a clear concept or idea, a good chemical starting point, time to allow iterative evolution, intense concentration and relentless commitment were the keys to success [1,2]. They believed that lack of commitment and technology driven projects are contributors to failure. The success stories in this issue describe the ideas that initiated the projects, the chemical starting points and the iterative processes used to identify the new medicines. Steven Frye of GSK chronicles the successful path to the discovery of the dual 5α reductase inhibitor dutasteride. He explains the origination of the idea for a once daily dual 5α-reductase inhibitor, the chemical starting point from steroid substrate analogs and past experience with finasteride, and the use of dog as an iterative model to optimize pharmacokinetics. The knowledge gained from experience with finasteride, the first 5α-reductase inhibitor, was used to hypothesize that a dual acting mechanism-based inhibitor is required to achieve greater clinical suppression of dihydrotestosterone and clinical efficacy against benign prostatic hyperplasia. The efforts of the GSK scientists eventually proved the hypothesis correct. Klaus Klumpp and Bradford Graves of Roche describe the discovery of the orally active influenza neuraminidase inhibitor, Tamiflu. Previous influenza neuraminidase inhibitors had high affinity but poor pharmacokinetic properties because of the polar charged character of the binding site. The idea was to find a molecule with less polarity and that still retained the activity. Starting with transition state mimics, they found a subtle conformational change in the active site that exposed a non-polar surface allowing a molecule to have both high binding affinity and drug-like properties. Karen Lackey of GSK recounts the path to discovery of Lapatinib, a dual EGF receptor/ErbB-2 kinase inhibitor currently in phase III studies for cancer. She points out that the idea was to target the two receptors with quinazoline-like compounds. She emphasizes how increased knowledge about the target and chemical series assisted the evolution of the efficacy and mechanism of action assays. A key breakthrough for their work was the discovery of molecules with cellular potency against both isoforms of the EGF receptor. A mathematical index is described which was used to formulate the medicinal chemistry plan. Retrospectively, it was found that these molecules had a unique binding mode to the kinase. These three successful drug discovery examples all have in common a clear idea of what they wished to achieve, good chemical starting points and evolved iterative processes to optimize the drug candidates. Janssen and Black identified the time required for iteration as a potential barrier to success [1,2]. A more rapid iteration may occur when experience from past drug discovery success can be used to guide current research. Past experience can also help define when a compound is sufficiently optimized (when there have been sufficient iterations). A review of the biochemical mechanism of action of new molecular entities approved by the US FDA between 2001 and 2004 suggests that the mechanism of drug action will contribute to a drug's therapeutic index. The potential for mechanism-based toxicity was identified as a key determinant of a drug's mechanism of action. Binding mechanisms will evolve for targets with no mechanism-based toxicity that maximize the effect at the lowest drug concentration by avoiding mass action competition to minimize off-target toxicities, whereas drugs with a potential for mechanism-based toxicity require a mechanism to minimize toxicity while retaining efficacy. Targeting drug targets that have mechanism-based toxicity has a greater risk requiring early iterative optimization of both efficacy and toxicity. Awareness of rules based on past drug discovery experience should facilitate drug discovery by decreasing the time required for the iterative evolution of molecules with the characteristics to be a medicine...........