Drug discovery route

The drug discovery route to rizatriptan (1) began with the preparation of 1-(4 -nitrobenzyl)-l,2,4-triazole 5 using 4-nitrobenzyl bromide (4) and 1,2,4-triazole. (Scheme 4.1). Benzylation of the sodium salt of 1,2,4-triazole prepared with NaH was not regioselective and afforded a 1.5 1 mixture of l-(4 -nitrobenzyl)-1,2,4-triazole (5) and its regioisomer, 4-(4 -nitrobenzyl)-l,2,4-triazole. The desired isomer 5 was isolated in 52% yield after silica gel chromatography. Hydrogenation... 

The drug discovery route to compound 1 started out with the expensive and poorly available boronic acid 2, which was coupled with aryl bromide 3 (Scheme 8.1). Hydrogenation of the resulting pyrrole 4 provided the racemic pyrrolidine 5. At... 

This process route replaced the drug discovery route that utilised an expensive boronic acid as starting material and yielded racemic 9 thus requiring an inefficient chiral separation at the end of the sequence. 

After preliminary evaluation of the discovery route (scheme 1), we concluded that the overall yield of RWJ-26240 should be improved and that the use of NaCNBH. should be eliminated, since it produces a waste stream containing HCN or NaCN. Replacement of the expensive silver reagent, silver acetate, would permit significant cost reduction. The copper-catalyzed palladium coupling step would lead to palladium as a contaminant in the final product.177 Since a drug substance containing palladium would not be acceptable, this step would also have to be revised. 

Donadio, S., Monciardini, P., Brandi, L., Sosio, M., and Gualerzi, C. O. (2007). Novel assays and novel strains—Promising routes to new antibiotics Expert Opinion on Drug Discovery. Accepted for publication. 

Jain, K. 2001. Proteomics delivering new routes to drug discovery, part 2. Drug Discovery Today. 6(16), 829-832. 

O Connor, K.A. and Roth, B.L. (2005) Finding new tricks for old drugs an efficient route for public-sector drug discovery. Nature Reviews. Drug Discovery, 4 (12), 1005-1014. 

Lead optimization of new chemical entities (NCEs) based on pharmacokinetic behavior plays a major role in modern drug discovery. Despite advancement of drug delivery methods, the oral route remains the most frequent route of administration for approved new drugs. Therefore, during lead optimization it is essential to identify NCEs with sufficient oral absorption predicted using a variety of in vitro and in vivo assays. It is well recognized that in order for a NCE to achieve reasonable oral absorption, it will need to have adequate aqueous solubility, as well as intestinal permeability [1], Recent advancements in chemistry, such as parallel and combinatorial synthesis, have resulted in a multifold increase in the number of compounds that are available for evaluation in new drug discovery. Furthermore, a variety of improved structural chemistry... 

Oral bioavailability is one of principal pharmacokinetic properties in drug discovery. It represents the percentage of an oral dose that is available to produce pharmacological actions, in other words, the fraction of the oral dose that reaches the system circulation in an active form. By the definition, when a drug is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes, especially orally, its bioavailability decreases due to incomplete absorption and first-pass metabolism. 

Jain, K. (2001). Proteomics delivering new routes to drug discovery, part 2. Drug Discovery Today 6(16), 829-832. Kassel, D. (2001). Combinatorial chemistry and mass spectrometry in the twenty-first century drug development laboratory. Chem. Rev. 101(2), 255-267. 

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