Although many academic chemists consult with firms and agencies, virtually none have formal training in this useful art. Furthermore, there is little in the way of formal literature on the topic other than a few books [1] and some trade magazine articles directed toward industrial managers, engineers, and clinicians. Practices vary considerably depending upon the skills and experience possessed by the consulting chemist and the environment in which he/she practices as well as the needs of the client. In this chapter, the author offers several observations based on over 40 years of continuous experience consulting at various levels with small and large firms in the pharmaceutical industry and with governmental, academic, and private agencies. The reader should not suppose therefore that this chapter is comprehensive or that it deals with every aspect of chemical consulting, given the intrinsically multifaceted nature of this activity. Furthermore, the proprietary nature of this activity restricts one’s ability to illustrate points by specific examples. Nonetheless, the author hopes that the following account contains interesting and helpful matter to those who are thinking of consulting or to those who may be thinking of engaging a consultant.

Need for Chemical Consultants in Drug-Seeking Campaigns

One of the particular virtues of consultants is that they are cheaper than hiring a collaborator and do not receive fringe benefits. Furthermore, the relationship is regarded as temporary, so parting company is not normally traumatic to either party. The client usually defines the issue and provides the necessary internal background and the expectations. The consultant asks strategic questions and adds his/her independent thoughts. This relationship requires mutual trust.

In a drug-seeking campaign as in most scientific undertakings, each answer uncovered raises several alluring questions. This can all too easily lead to project drift. One important contribution that a consultant can make is to help keep the project on course.

Among the types of projects that an experienced chemical consultant can often help with are, for example, in assessing the degree of novelty and utility in heritage or potential chemical compound collections; selection of useful hits for further work from the results of screening assays or in open source data; anticipating and avoiding problems with toxicity and pharmacokinetic factors; design of potentially useful ligands for the targets being addressed; improvement of the desirable properties of early leads through efficient analoging; synthetic design; alteration of chemical pathways to avoid development problems later; redesign of synthetic routes to facilitate the preparation of bulk quantities at an attractive cost; interpreting apparently anomalous reaction results and devising schemes to avoid them; devising suitable chemical methods of analysis; designing suitable backup alternatives; and constructing patents that provide adequate patent coverage.

The amount of effort and money involved in introducing a novel pharmaceutical agent into the market place can be very substantial. A drug-seeking campaign can consume a decade or more and require the expenditure of many millions of dollars when there is no obvious structural guidance from which to start. Unfortunately, people are notoriously poor at making decisions in the face of complex and often uncertain or conflicting data when the stakes are high. A poor decision can result either in significant wastage in precious resources through synthesis and evaluation of compounds that ultimately fail or in failure to proceed with compounds that ultimately would have succeeded. The costs of drug-seeking campaigns usually escalate rapidly as the campaign goes on. If a failure is to be the ultimate outcome, it should happen as early as possible and be based on solid scientific evidence. If the properties of a lead compound or series are truly outstanding, or, conversely, are appalling, then decisions are easy. Decision is vexingly difficult when properties lie midway between these extremes! As the work proceeds, one quite often becomes seduced by the belief that success can lie just ahead. Chemists are by nature optimists; otherwise, they would not be in this field. One must guard against the tendency to behave like a compulsive gambler believing that by making just one more analog, success will be at hand! Overestimation of the prospects for success is endemic. Receiving credible advice from a skilled practitioner allows one to cope better with these pressures. This is particularly true if the ultimate decision is that the project should be terminated. The consultant can be of great help in making these vexing decisions.

Advice from an experienced chemist who has successfully navigated these troubled waters is no guarantee of success but does considerably enhance the comfort level of those with responsibility for the effort. Under the best of circumstances, many more molecules fail than not.

Failure stems from many causes, not all of which are easily anticipated. A faulty theory of the molecular cause of a disease and therefore of a posited molecular treatment, a biological test system that fails to address the key characteristic required, an unanticipated difference in species response to treatment, an unavoidable adverse side effect, poor water solubility, adverse pharmacokinetic and pharmacodynamic features, idiosyncratic toxicity, unexpected failure to achieve adequate and defensible patent protection, and so on, are all challenges that must be recognized early and dealt with. Some of these are unavoidable when they happen, but the scientist, assisted by the consultant, has the responsibility of anticipating likely problems and devising means of dealing successfully with them or deciding to change directions.

Temporary problems blocking further progress almost always occur in drug seeking. These must be dealt with expeditiously since time loss is an implacable enemy. When a workable solution does not readily present itself to the researcher, consultation can be extremely useful. In this context, the consultant can supply specialized knowledge or capacities not present in a firm at that time. If problems of this type occur repeatedly, a longer term relationship may be required until this problem disappears. When such problems are found to be widespread in a firm, the consultant can deal with this in an efficient manner by developing and presenting in-house an interactive short course on specialized topics such as the relationship between pharmacokinetic and pharmacodynamic characteristics and the structure of molecules, on the strengths and weaknesses of fragment-based drug discovery, on newer methods of synthesis and novel reagents, and the like.

The consultant will usually be working with very intelligent and highly trained persons who have already given a problem thoughtful consideration without success or not be confident that their solution will be the best approach. Clients often know their individual project very well and are enthusiastic about it. They will resent trivial or obvious suggestions. Giving cogent reasons for suggestions goes a long way toward developing a productive relationship. Consulting, like water, does not flow uphill. Credibility develops naturally when advice works more often than it fails.

The need or desire for consultation often develops due to the intense special­ization that can develop due to an individual’s faithfulness in carrying out his/her assigned role in the firm. Thus, scholarship and experience may over time become narrow. In other cases, the need may be associated with newness on the job or significant changes in the firm’s direction. Thus, consultation is especially useful when a laboratory is planning to or has decided to enter a significantly new area since internal prior experience may not be especially helpful. Sooner or later it will happen that the internal knowledge outgrows the contribution that a consultant can make. In long-term relationships, the client will know the consultant’s manner of thinking rather well and can anticipate the advice most likely to be proffered. When this occurs, it is time to move on.

Role for Chemical Consultation in Open Drug Discovery Programs

Open drug discovery is a comparatively new approach to drug seeking as is apparent from the information elsewhere in this work. Traditionally, drug seeking has been a highly proprietary enterprise carried out behind closed doors. This characteristic still largely characterizes discovery research in industry. Working in this environment requires some adjustment for academics who consult because the essence of academic work is the wide sharing of new science at the earliest opportunity. Open drug discovery lies somewhat in between these extremes. Some companies, however, are beginning to open a portion of their books to outsiders as a public service. Often these laudable activities involve releasing potentially useful data and compounds to be applied to “orphan diseases” to be pursued in other hands. These are severe health problems such as malaria, tuberculosis, or various tropical diseases that the company, for economic reasons, cannot pursue with the realistic expectation of providing their shareholders with a satisfactory return on their investment. This is, after all, the essence of capitalism. Companies are not charities.

Unfortunately, by and large, the places where these public health problems are widespread and endemic do not have the human and economic resources to attack them successfully. Historically, these problems have been attacked inefficiently. In an attempt to deal with this otherwise intractable problem, some forward-thinking firms are placing compounds and data in the public domain in the hope that outside individuals will build on this information and develop therapy for these prevalent but neglected diseases.

Thus, both experienced and comparatively naive scientists are beginning to have access to masses of data from which to pursue potential cures. A useful parallel can be seen in the availability of commercial and academic compound libraries stemming from combinatorial chemistry mated with high-throughput screening efforts especially as occurs with the NIH roadmap. Both of these efforts produce “hits” that require further refinement for new purposes. Experience shows that many of the hits uncovered fail to have the intrinsically desirable characteristics likely to elevate them to the “lead” category and thence onward to candidate drug and actual drug status. Selecting among these is an art requiring experience and judgment. This is largely a multifactorial exercise in pattern recognition in which experience is especially helpful. The more one knows in such exercises, the luckier one is likely to be. Characteristics particularly important for the treatment of orphan diseases in impoverished and/or remote populations are that the agents be cheap, orally active, be convenient to consume, require once daily dosing, be effective rapidly, and require short-term treatment schedules. This is not easy to accomplish when added to all of the other characteristics that must be gotten right. Chemists new to drug seeking can profit significantly from the advice of experienced consultants in making these decisions.

Many organic chemists have an excellent background and significant experience in synthesis but have little formal training in human biology. This is a potential handicap in drug seeking. Experienced medicinal chemists have a background that blends these two disciplines in a practical way. This is especially useful when faced with the necessity of choosing a few compounds for further work from a series of hits from a high-throughput screening program. Selecting advancable compounds requires a judicious balancing of a couple of dozen significant chemical and biological characteristics. Furthermore, these characteristics differ individually in importance from series to series. Thus, the problem is anything but trivial. Organic chemists know how to make compounds. Medicinal chemists know what is worth making for medicinal purposes.

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