Crixivan , development

Figure 2.2. Timeline of fast-track development of an HIV protease inhibitor, indinavir Crixivan) by Merck through a project research team approach. Adapted from Merck s account on Crixivan development.

For developing new drugs => to discover molecules with structural attributes that enhance certain medical effects or reduce undesired side effects => e.g. Crixivan (an HIV protease inhibito, Chapter 2). 

Norvir (ritonavir, ABT-538) by Abbott (Kalamazoo/MI, USA) in phase II demonstrated a 100-fold reduction of viral count, more than Crixivan and AZT. The threefold enhancement of CD4-T cell count after 12 weeks is also an improvement over AZT. However, even ABT-538 develops resistances, albeit more slowly than Crixivan. Hepatic side effects limit doses to 600 mg twice daily. Ritonavir has high oral bioavailability, about 78% in rats, good solubility (5.3 g IT1 (pH 7.4) to 6.9 g L-1 (pH 4.0)), and a plasma half-life of 1.2 h (Kempf, 1995). The molecule is difficult to produce in phase II, the overall yield in production was 2% ( ) in addition, the product was cherry-red. The combination of ritonavir and saquinavir has also been reported to dramatically increase saquinavir plasma concentrations (by as much as 50-fold). Ritonavir is believed to act by inhibiting cytochrome P450 (CYP 3A4), the enzyme responsible for saquinavir first-pass metabolism. 

Beyond lead optimization, the cost savings for final marketed drug production may be dramatic if the final compound is accessible via MCR methodology, as opposed to a multi-step route. Indeed multi-step chemical process development is often a bottleneck in drug discovery. An excellent example is the HIV protease inhibitor Crixivan , which will be discussed in due course [6]. 

The challenge with Crixivan, as with any drug, is to make it efficiently—high yields few steps. It has five stereogenic centres, so the chemists developing the synthesis needed to address the issue of diastereoselectivity. And it is a single enantiomer, so an asymmetric synthesis was required. We can start by looking at some likely disconnections, summarized in the scheme above. They are all disconnections of the sorts you met in Chapter 30, and they all correspond to reliable reactions. 

Jacobsen epoxidation turned out to be the best large-scale method for preparing the cis-amino-indanol for the synthesis of Crixivan, This process is very much the cornerstone of the whole synthesis. During the development of the first laboratory route into a route usable on a very large scale, many methods were tried and the final choice fell on this relatively new type of asymmetric epoxidation. The Sharpless asymmetric epoxidation works only for allylic alcohols (Chapter 45) and so is no good here. The Sharpless asymmetric dihydroxylation works less well on ris-alkenes than on trans-alkenes, The Jacobsen epoxidation works best on cis-alkenes. The catalyst is the Mn(III) complex easily made from a chiral diamine and an aromatic salicylaldehyde (a 2-hydroxybenzaldehyde). 

Advisory committee members were clearly impressed by Merck s presentation but did turn the discussion more directly to Crixivan s side effects. The company acknowledged that some patients had developed a condition known as hyperbilirubinemia (an increase of bile in the bloodstream that can bring on jaundice), while others suffered from nephrolithiasis (kidney stones) during the clinical trials. Since less than 1 percent of patients experienced increased bilirubin levels, the company had not modified the protocol. The kidney stones, on the other hand, led clinicians to recommend that patients increase their fluid intake. Phase III studies showed a limited incidence of this side effect, indicating that greater consumption of water had helped mitigate formation of kidney stones. 

Lin, J. H., Ostovic, D. and Vacca, J. P. The integration of medicinal chemistry, drug metabolism and pharmaceutical research and development in drug discovery and development story of Crixivan, an HIV protease inhibitor, Pharm. Biotechnol. Integration of Pharmaceutical Discovery and Development, 11 233-255. 1998. 

Figure 35.22 Compound optimization. Four compounds are evaluated for characteristics including the IC50 (the compound concentration required to reduce HIV replication to 50% of its maximal value), log P, and c ax (the maximal concentration of compound present) measured in the serum of dogs. The compound shown at the bottom has the weakest inhibitory power (measured by IC50) but by far the best bioavailability (measured by Cmax)- f compound was selected for further development, leading to the drug indinavir (Crixivan).

The development of practical routes to the title compound has been the focus of intensive research effort since cis-aminoindanol was identified as a critical component of the highly effective HIV protease inhibitor indinavir (Crixivan ).7,8 Reported routes include racemate synthesis followed by resolution via diastereomeric salts,8 enzymatic resolution,9 and asymmetric hydroxylation.10 However, the use of a modified Ritter... 

Lin JH, Ostovic D, Vacca JP. The story of Crixivan , an HIV protease inhihitor. In Borchardt RT, et al, eds. In Integration of Pharmaceutical Discovery and Development—Case Histories. New York Plenum Press, 1998 233—255. 

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