Medicinal chemistry origins

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]. 

Thiazole and its derivatives are useful compounds in medicinal and agricultural chemistry. The thiazolium ring is present in vitamin B1 and its coenzyme form is important for the decarboxylation of a-keto acids [74]. This heterocyclic system has broad application in drug development for the treatment of inflammation [75] and bacterial [76] and HIV infections [77]. Hence the thiazole nucleus has been much studied in organic and medicinal chemistry. Originally it was synthesized by the Hantzsch reaction (a-halo ketones with thioamides or thioureas) (Equation 4.38) [78]. 

Web in the life of the medicinal chemist. One may see the development of alerting services for the primary medicinal chemistry journals. The Web-based information search process could be replaced by a much more structured one based on metadata, derived by automated processing of the original full-text article. To discover new and potentially interesting articles, the user subscribes to the RSS feeds of relevant publishers and can simply search the latest items that appear automatically for keywords of interest. The article download is still necessary, but it may be possible for the client software to automatically invoke bibliographic tools to store the found references. Another application of the Chemical Semantic Web may be as alerting services for new additions to chemical databases where users get alerts for the new additions of structures or reactions. 

Even though there are a few drawbacks, as mentioned above, we felt that the Medicinal Chemistry route was straightforward and we should be able to use the original synthetic scheme for a first delivery with modifications as follows ... 

Our approach for chiral resolution is quite systematic. Instead of randomly screening different chiral acids with racemic 7, optically pure N-pMB 19 was prepared from 2, provided to us from Medicinal Chemistry. With 19, several salts with both enantiomers of chiral acids were prepared for evaluation of their crystallinity and solubility in various solvent systems. This is a more systematic way to discover an efficient classical resolution. First, a (+)-camphorsulfonic acid salt of 19 crystallized from EtOAc. One month later, a diastereomeric (-)-camphorsulfonic acid salt of 19 also crystallized. After several investigations on the two diastereomeric crystalline salts, it was determined that racemic 7 could be resolved nicely with (+)-camphorsulfonic acid from n-BuOAc kinetically. In practice, by heating racemic 7 with 1.3equiv (+)-camphorsulfonic acid in n-BuOAc under reflux for 30 min then slowly cooling to room temperature, a cmde diastereomeric mixture of the salt (59% ee) was obtained as a first crop. The first crop was recrystallized from n-BuOAc providing 95% ee salt 20 in 43% isolated yield. (The optical purity was further improved to -100% ee by additional recrystallization from n-BuOAc and the overall crystallization yield was 41%). This chiral resolution method was more efficient and economical than the original bis-camphanyl amide method. 

Efavirenz (1) was chosen over compound 2 as a developmental candidate in 1993 based on its better antivirus activities, especially against resistant strains [1, 17]. Efavirenz is the first HIV non-nucleoside reverse transcriptase inhibitor (NNRTI) which was approved by the FDA on September 21, 1998. The original Medicinal Chemistry method to prepare Efavirenz is depicted in Scheme 1.14. 

Scheme 1.14 Original Medicinal Chemistry route for Efavirenz (1).

The original Medicinal Chemistry route was straightforward but, from a process chemistry point of view [20], several problems were identified at the beginning of the project and some of them were quite similar to those for the previous development candidate ... 

Synthesis of pyrazole 3 by the Medicinal Chemistry route was straightforward from N-Boc isonipecotic acid (45), so we utilized the route after some optimizations, as summarized in Table 2.4. The key 1,3-diketone intermediate 48 was prepared from 45 without issues. A minor problem in the original route was the exothermic nature of the Claisen condensation between methyl ketone 47 and methyl phenylacetate. Slow addition of l.lequiv of methyl phenylacetate to a mixture of 47, 0.2equiv of MeOH, and 2.5equiv of NaH in THF at room temperature solved this exothermic issue and reduced the amount of self-condensation of... 

While the Medicinal Chemistry route was adequate for the initial discovery stage of drug development, viewed against the need to make multiple kilograms or much larger quantities of compound 1 efficiently, the original route suffered from a few obvious shortcomings. 

In the original Medicinal Chemistry route, protection of the phenolic OH with a benzoate was carried out prior to N-methylation. In order to simplify the process, the direct N-methylation of hydroxypyrimidinone 3 was investigated. To our delight, methylation of 3 gave a mixture of the desired N-methyl product 31 and the undesired O-methyl by-product 32 as a 70 30 mixture (Scheme 6.7 path b). Surprisingly, methyl ethers 28-30 were not observed at all (Scheme 6.7 path a). 

The original medicinal chemistry synthesis of ether 18 involved reaction of alcohol 10 with racemic imidate 17 in the presence of a catalytic amount of TfOH and furnished an approximately 1.1 1 mixture of 18 19 (Scheme 7.3) [1], We thought it worthwhile to reinvestigate this reaction with chiral imidate 67 in an effort to explore the diastereoselectivity of the etherification. 

Cyclic. S -Mannich bases are rarely encountered in medicinal chemistry. The (R)-thiazolidine-4-carboxylic acids (11.113, Fig. 11.15), which are used as derivatives and chemical delivery systems for L-cysteine (11.114), provide an excellent example of S-Mannich bases. These compounds underwent activation by two distinct mechanisms, directly by nonenzymatic hydrolysis to cysteine and the original aldehyde (Fig. 11.15, Pathway a), and oxidatively (Pathway b) [138]. The latter route involved first oxidation by mitochondrial enzymes to the (f )-4,5-dihydrothiazole-4-carboxylic acid (11.115), followed by (presumably nonenzymatic) hydrolysis to /V-acylcysleine, and, finally, cytosolic hydrolysis to cysteine (11.114). 

Scheme 5. Original Synthesis of Enprophylline by the Medicinal Chemistry Department at Astra.

Mitscher, Lester A., and Apurba Dutta. Combinatorial Chemistry and Multiple Parallel Synthesis, John Wiley fit Sons, Inc. Available online. URL http //media.wiley.eom/product data/excerpt/82/04713702/ 0471370282.pdf. Originally published in Burger s Medicinal Chemistry and Drug Discovery, edited by Donald J. Abraham. Vol. 2, Drug Discovery and Development. Hoboken, N.J. Wiley, 2003. 

Estiu, G., Greenberg, E Harrison, C.B., Kwiatkowski, N.P., Mazitschek, R., Bradner, J.E. et al. (2008) Structural origin of selectivity in class 11-selective histone deacetylase inhihitors. Journal of Medicinal Chemistry, 51, 2898—2906. 

The impact of small molecules on the acetylation status of histones has attracted the interest of the medicinal chemistry community for almost a decade now. Nevertheless, the fast and reversible increase in cellular histone acetylation in the presence of -butyrate was already recognized in 1977 by Riggs et al. (Fig. 3) [30]. Two years later, it was proven that n-butyrate, among some related and less active small linear aliphatic carboxylates, was a noncompetitive inhibitor of histone deacetylating enzymes [31-34]. More than ten years after the initial interest in -butyrate, Yoshida et al. showed that trichostatin A (TSA, Fig. 3), originally reported as an antifungal agent [35],... 

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