behin the particularl nd the high attrition of drug candidates had the ext ed impact on drue dis ustry wh aders are umbe Rece some stunning,i disturbing er develo ely 18 billion Us dollars (exeludin iden ening of rando co a range of the total expendi the advent of rand ures du. preceding era and ed by pe of drus ering the d that"the of 93%and pat y r that disprop g.litigation).as ed to to reach.The of fa inical develo f ided fact ed and nd in the medicinal che n the olecule likely to displa Figure 1.Nu design programs in wh w) are fror the tare The imization from trial and ed 200 and od ab in tion c compound.the s alled Lipinski rule eight less than 500 Dalton (MW<500):calculated partition Angrw.Chem.int.Ed 2014.52 9128- andte.org 9129 2. Current State of Affairs in the Drug Discovery and Development Process Pressures from the sales of generic drugs and the high attrition of drug candidates are currently plaguing the pharmaceutical industry while its leaders are scrambling for new models and paradigms to improve the situation.[3–24] Recent analyses[11] reveal some stunning, if not disturbing statistics. The cost of developing a drug as of 2010 stood at approximately 1.8 billion US dollars (excluding target iden￾tification and validation and overhead costs; perhaps a range between 1–2 billion US dollars may be more descriptive) and rising. Clinical trials accounted for 63% of the total expendi￾tures, while the cost of preclinical drug discovery and development was estimated to be only 32% of the total cost. The duration of the process from target validation to approval was on average 13.5 years. Success rates (probability of the success of drug candidates entering the clinical pipeline/ Phase I) were estimated at 7% for small molecules and 11% for biologics (attrition rates of 93% and 89%, respective￾ly).[11] It is clear that disproportionate resources are expended on late-stage development (i.e., clinical trials) and post￾approval activities (e.g., marketing, litigation), as opposed to early-stage discovery and preclinical development. The post-penicillin period was a golden era for the pharmaceutical industry with many drugs being approved steadily and at increasing rates until the recent notable sluggish achievement of drug approvals. Indeed, the global number of drugs approved annually during the period 1981– 2013 did not increase significantly as expected (see Figure 1). Surprisingly to some, this phenomenon occurred despite the impressive strides made recently in chemistry and biology, the two major disciplines behind the process. It is particularly disappointing that the human genome project has not as yet had the expected impact on drug discovery, as measured by the number of drug approvals (see Figure 1), although there is no denying its beneficial impact on science and its future potential. Disappointingly, other developments that started in the 1990s, such as the combinatorial chemistry and high￾throughput screening of random compound libraries, also failed to impact dramatically the drug discovery and develop￾ment process despite their early promises. It is interesting to note that the advent of random combinatorial chemistry in the late 1980s coincided with the downsizing of natural products chemistry that had proved so productive in the preceding era and had been sparked by penicillins success. To the causes of the recent slowdown in drug approvals must also be added the fact that “the low-hanging fruits” (e.g., diseases associated with known pathogenesis, druggable biological targets, predictive in vitro and in vivo assays, and reliable clinical endpoints) have already been picked, and the realization that those remaining are becoming increasingly more challenging to reach. The blame of failure to deliver better drug candidates, however, cannot entirely be placed on these developments. Rather, it appears that the actual design of the synthesized molecules during the lead discovery and optimization phase of the process in past eras was sometimes misguided, a fact recognized and pointed out by medicinal chemists and other biomedical researchers. Indeed, a series of recent reviews and commentaries convincingly argue the case for improvements and new directions in the practices of drug design of the last few decades.[3–24] Currently, medicinal chemists have at their disposal, in addition to their experience and intuition, a number of guidelines and principles that have been developed over recent years to assist them in their endeavors as they proceed to design and optimize lead compounds to drug candidates. In most pharmaceutical companies, drug designers are also using computational models to select the best molecules for syn￾thesis. Such computational models help them understand whether the molecules are likely to display the desired ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties. In addition, they employ several structure-based drug design programs in which X-ray crystal structures help them identify the optimum small molecules to fit the targeted receptors. The optimization process involves reiterative molecular design (computer-aided or not), syn￾thesis of the designed molecules, and biological evaluation of the synthesized compounds. Indeed, most structure–activity relationships (SARs) and other structure–property relation￾ships are presently derived from trial and error based experimentation rather than computational chemistry or other reliable predictive methods. The first systematic guide￾lines to be introduced in medicinal chemistry were those delineated by Lipinski and his collaborators in their landmark papers in 2001[4] and 2004.[5] For good absorption or perme￾ability of a compound, the so-called Lipinski rule of five (RO5) stipulates limits for certain parameters [i.e., molecular weight less than 500 Dalton (MW< 500); calculated partition Figure 1. Number of all new approved drugs during the 1981–2013 time period (globally, modified from Ref. [49]). *Data for 2011, 2012, and 2013 are from the FDA[71] (global data not availiable as of this writing). K. C. Nicolaou, born in Cyprus and edu￾cated in the UK and USA, holds the Harry C. and Olga K. Wiess Chair in Chemistry at Rice University. The impact of his work in chemistry, biology, and medicine flows from his contributions to chemical synthesis as described in over 750 publications. His commtiment to chemical education is re￾flected in his book series Classics in Total Synthesis and monograph Molecules That Changed the World, and his training of hundreds of graduate students and postdoc￾toral fellows. Angewandte Chemie Angew. Chem. Int. Ed. 2014, 53, 9128 – 9140 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org 9129