Selective medicinal route

In this chapter the development of the synthesis of taranabant will be presented. In Section 9.1, we focus on evaluation and optimization of the Medicinal Chemistry route, and development of an asymmetric version of this initial route. In Section 9.2 the discovery and implementation of a new asymmetric route will be discussed, and extensions of the utility of this chemistry will also be discussed. Finally, the factors involved in selecting a route as a potential manufacturing approach for taranabant are presented. 

The first NNTRI drug candidate 2 was selected for development in 1992. Compound 2 exhibits very potent antivirus activity of IC50 = 12nM (inhibition HIV-1 RT using rC-dG template/primer). The Medicinal Chemistry original preparation route is depicted in Scheme 1.1 [2]. 

The majority of medicines today are formulated as tablets [1], Tablets are formulated rapidly and economically, and they have high patience compliance. Also, many compounds, such as aspirin, degrade rapidly in solution and are formulated in solid dosages to increase stability [2]. Drug substances that are oils, liquids, and solids may be formulated into capsules, tablets, lyophiles, creams, or microsuspensions. Administration may be through ingestion, injection, topical application, inhalation, and other routes. The reader may consult other texts for discussion of formulation options [1,3]. Formulations are selected for stability and the ability to best deliver the active agent to the affected area of the patient or consumer. 

Exploitation of commercially available analogues of the selected hits is often an early step in the first round of SAR studies. This is usually followed by the use of basic medicinal chemistry to modify these analogues to sample a reasonable fraction of the overall chemical space. In parallel it is essential to spend time researching synthetic routes to generate the basic scaffold and selected syn-thons with the objective to incorporate more, extended, or diverse functional groups and thns expand the sampled chemical space considerably. 

Various purines have successfully been employed in medicine for some decades. The effort to obtain compounds with a greater selective efficacy without the unwanted side-effects then those of the parent purines, stimulated the study of annulated compounds. One route fulfilling this aim was the annulation of an heterocycle to the purine ring system. 

One review of a synthetic nature covered new routes to pyridazino-fused ring systems <04SL1123>. In addition to this, there were two reviews focusing on specific medicinal applications of some diazines. One covered the design, synthesis and SAR of 5-[(l-substituted) alkyl (or vinyl)] pyrimidine nucleosides as potential inhibitors of herpes viruses <04MI2749>, and the other described 4-thiophenoxy-N-(3,4,5-trialkoxyphenyl)pyrimidine-2-amines as potent and selective inhibitors of the T-cell p561ck tyrosine kinase <04MI747>. 

See also Nucleotide Analogs in Selection, Deoxycytidine Kinase, BrdUrd, Salvage Routes to Deoxyribonucleotide Synthesis, Nucleotide Analogs in Medicine... 

Many of the procedures used in conventional toxicity testing with animals have arisen by an apparently empirical process (e.g., period of exposure and selection of dose levels). Safety studies are performed with a variety of experimental animals, including rodents, rabbits, nonhuman primates, and farm animals, before progressing to studies with human volunteers, and other animals in the case of veterinary medicines. The individual study designs vary with the chosen animal species, route of administration, duration (dependent on the proposed or estimated exposure in... 

Factors guiding the selection of specific opioid compounds for pain treatment include potency, pharmacokinetic characteristics, and the routes of administration available. A more potent compound could be useful when high doses of opioid are required so that the medicine can be given in a smaller volume. Duration of action also is an important consideration. In cases where a lower addiction risk is required or in patients unable to tolerate other opioids, a partial agonist or mixed agonist-antagonist compound might be a rational choice. 

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