Medicinal chemist

Readers interested in medicinal chemistry can obtain an excellent overview ft om the book The Practice of Medicinal Chemistry, edited by Wermuth [1]. The first edition is nicknamed The Green Bible by medicinal chemists. "The Red Bible written by Bbhm, Klebe, and Kubinyi describes the development of new drugs [2]. An overview of different classes of drugs and their mechanisms of action is given by Mutschler [3]. 

The natural prostanoids have myriad biological effects and held great promise as potential therapeutic agents in numerous diseases. The natural prostanoids, however, also have three notable drawbacks which medicinal chemists have tried to overcome by molecular modification in order to produce acceptable dmg candidates. These drawbacks are rapid metaboHsm which results in lack of activity if taken orally and a short duration of action, numerous side effects due to their multiplicity of biological activities, and poor chemical stabiUty, a characteristic especially pronounced in PGE, -D, and -I stmctures. 

J. Ackerman, DiagnosticMgents, iu A. Burger, ed.. Medicinal Chemist, 3rd ed.. Part II, John Wiley Sons, Inc., New York, 1970, Chapt. 67, pp. 1686—1699. P. K. Knoefel, ed.. International Encyclopedia of Pharmacology and Therapeutics, Sect. 76, Pergamon Press, Oxford, U.K., 1971. 

The modem dmg discovery team consists of medicinal chemists, biologists, metaboHsm and pharmacokiaeti.es speciaHsts, and toxicologists working together to improve dmg selection. 

A chance observation made some time prior to the full structural elucidation of cocaine in fact led to one of the more important lasses of local anesthetics. It was found that the simple ethyl e. ter of p-aminobenzoic acid, benzocaine (25), showed activity. 1-. a local anesthetic. It is of interest to note that this drug, I 1rst introduced in 1903, is still in use today. Once the struc-iiire of cocaine was established, the presence of an alkanolamine iiiniety in cocaine prompted medicinal chemists to prepare esters "I aminobenzoic acids with acyclic alkanolamines. Formula 26 11 presents the putative relationship of the target substances with cocaine. 

The isosteric relationship of benzene and thiophene has often led medicinal chemists to substitute the sulfur containing heterocycle for benzene drugs in biologically active molecules. That this relationship has some foundation in fact is attested by the observation that the resulting analogs often possess full biologic activity. Alkylation of the diamine, 71 (obtained from aniline and the chloroethylamine), with 2-chloromethylthiophene affords the antihistamine methaphenylene (72) The correspond-... 

It has become almost an article of faith among both pharmacologists and medicinal chemists that drugs (and for that matter, hormones) owe their action to interaction with some receptors. 

Though dental afflictions constitute a very significant disease entity, these have received relatively little attention from medicinal chemists. (The fluoride toothpastes may form an important exception.) This therapeutic target Is, however, sufficiently Important to be the focus of at least some research. A highly functionalized piperazine derivative that has come out of such work shows prophylactic activity against dental caries. Condensation of the enol ether 1 of thiourea with ji-pentylisocyanate gives the addition product 1J. Reaction of this with diamine 78, derived from piperazine, leads to substitution of the methylthio moiety by the primary amine, in all likelihood by an addition-elimination sequence. There is thus obtained ipexidine (79). ... 

There are numerous natural substances that have useful therapeutic properties as well as other undesirable properties. From these starting points, medicinal chemists have improved on nature. For example, while extremely useful in the treatment of infection penicillin is not available by the... 

Since /1-lactams can be prepared via reactions of ester enolates with imines, these reactions are of great interest for synthetic and medicinal chemists. The synthesis of naturally occurring antibiotics and other physiologically active //-lactams is an objective of much current work. Though the stereocenters in those reactions are often established by addition of enolates to imines, they are discussed in Section D.1.6.1.3. In this section, only some basic results concerning //-lactams are presented. 

From a medicinal chemist s point of view, oxadiazoles are among the most important heterocycles as they are one of the most commonly used bioisosters for amide and ester groups [67]. As such it is hardly surprising that the two regioisomeric oxadiazole scaffolds received the most interest in the field of microwave-assisted synthesis using polymer-supported reagents. 

Today, computers are so ubiquitous in pharmaceutical research and development that it may be hard to imagine a time when there were no computers to assist the medicinal chemist or biologist. A quarter-century ago, the notion of a computer on the desk of every scientist and company manager was not even contemplated. Now, computers are absolutely essential for generating, managing, and transmitting information. The aim of this chapter is to give a... 

Unfortunately, the tension between the computational chemists and the medicinal chemists at pharmaceutical companies did not ease in the 1970s. Medicinal chemists were at the top of the pecking order in corporate research laboratories. This was an industry-wide problem revealed in conversations at scientific meetings where computational chemists from industry (there were not many) could informally exchange their experiences and challenges. (Readers should not get the impression that the tension between theoreticians and experimentalists existed solely in the business world. It also existed in academic chemistry departments.)... 

The situation was that as medicinal chemists pursued an SAR, calculations by the computational chemists might suggest a structure worthy of synthesis. Maybe the design had the potential of being more active. But the computational chemist was totally dependent on the medicinal chemist to test the hypothesis. Suddenly, the medicinal chemist saw himself going from being the... 

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