Process development, inhibitor

Neutralization to terrninate processing was effected by the polymeric acid layer of the covet sheet the onset of this reaction was controlled by the rate of permeation of the overlying polymeric timing layers. MobiUty of the transferred dyes was also reduced by reaction with a mordant contained in the image-receiving layer. A development inhibitor released from one of the timing layers by the alkaline hydrolysis of its precursor assisted in restraining further development and consequent additional dye release. 

Abstract This review provides an overview of the development of viral protease inhibitors as antiviral drugs. We concentrate on HlV-1 protease inhibitors, as these have made the most significant advances in the recent past. Thus, we discuss the biochemistry of HlV-1 protease, inhibitor development, clinical use of inhibitors, and evolution of resistance. Since many different viruses encode essential proteases, it is possible to envision the development of a potent protease inhibitor for other viruses if the processing site sequence and the catalytic mechanism are known. At this time, interest in developing inhibitors is Umited to viruses that cause chronic disease, viruses that have the potential to cause large-scale epidemics, or viruses that are sufQciently ubiquitous that treating an acute infection would be... 

Many substances can affect metabolic processes by influencing the activity of enzymes. Enzyme inhibitors are particularly important here. A large proportion of medicines act as enzyme inhibitors. Enzyme-kinetic experiments are therefore an important aspect of drug development and testing procedures. Natural metabolites are also involved in regulatory processes as inhibitors (see p.ll4). 

A third route developed by this group started with the commercially available alcohol 32," a compound which has also been the subject of considerable process development due to its use as a common intermediate in the synthesis of several HMGR inhibitors.Conversion of 32 to the 4-halo or 4-nitrobenzenesulfonate 33 followed by displacement with sodium cyanide provided 34 in 90% yield, which is the z-butyl-ester analog of 29. It was noted that this procedure was most scaleable employing the 4-chlorobenzenesulfonate 33a due to the instability of the 4-bromo and 4-nitro-analogs to aqueous hydrolysis. Ra-Ni reduction as before provided the fully elaborated side-chain 35 as the f-butyl ester (Scheme 8). 

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 (ft)-4-phenyl-2-oxazolidinonc auxiliary was used in the process development and scale up of Novartis purine nucleoside phosphorylase inhibitor PNP405 (16) (Scheme 23.2).43 Asymmetric alkylation of 17 with bromoacetonitrile provided a 7 1 diastereoisomeric ratio of crude 18. Recrystallization afforded 18 in 80% yield and >99% de. Simple addition of sodium borohydride in tetrahydrofuran (THF)-water at room temperature44 resulted in the desired y-cyano alcohol 19 and recovery of the auxiliary. 

Nor are the contributions to be made by p-lactam structures to the pharmaceuticals field over. The extraordinary developments of recent years in cholesterol absorption inhibitors (CAIs) based on the p-lactam ring deserve some mention, especially since Dr. T. K. Thiruvengadam in our chemical process development organization in Schering-Plough is the brilliant architect of one of the patented syntheses of this novel class of CAIs. His synthesis35 of Ezetimibe (Zetia), outlined in Scheme 13, serves to (a) introduce this new direction in the development of novel p-lactam medicinals and (b) end this excursion in the field of p-lactams. 

In summary, sunitinib maleate (1) is a multitargeted receptor tyrosine kinase inhibitor with potent anti-angiogenic and antitumor activity. It is approved for the treatment of advanced renal cell carcinoma and gastrointestinal stromal tumors, and is currently undergoing clinical trials for a number of additional malignancies. The discovery synthesis of 1 along with its process development approaches were described in this chapter. 

A concise and efficient synthesis of the potent reverse transcriptase inhibitor Elfavirenz [Scheme 3.130] by the DuPbnt-Merck process development groups entailed the removal of an A O-acetal under basic conditions.252 Oxidation of the N-p-methoxybenzy derivative 130.1 with DDQ at 0 °C generated the NtO-acetal 130.2 in quantitative yield. Treatment of 130,2 with sodium hydroxide in... 

Dale DJ, Draper J, Dunn PJ, Hughes ML, Hussain F, Levett PC, Ward GB, Wood AS. The process development of a scaleable route to the PDE5 inhibitor UK-357,903. Org. Process Res. Dev. 2002 6 767-772. 

As the understanding of specific enzymatic processes develops, both in the sense of their mechanisms and of their significance in human and pathogen biochemistry, the need for highly efficient and specific inhibitors will increase. An example of what is likely to be developed in the... 

The trials on this pilot facility go further to study more aspects regarding MEA loss rates, and the optimum quality and quantity of the inhibitors and stabilizers needed to improve the amine tolerance at high oxygen levels to avoid the formation of corrosive compounds. The research aims to complete the process development and to identify potential applications for utilization of the recovered CO2 and to establish appropriate... 

As discussed in Chapter 1, polymorphism is a common problem encountered in the synthesis of pharmaceuticals. In the process development for a drug candidate of reverse transcriptase inhibitor, six crystal forms were identified. The first pilot plant batch produced all Form III, not the desired Form I. The purpose of this example is to illustrate the development of a robust crystallization process to consistently grow the desired crystal form. 

A cost effective and easily scaled-up process has been developed for the synthesis of (S)-3-[2- (methylsulfonyl)oxy ethoxy]-4-(triphenylmethoxy)-1 -butanol methanesulfonate, a key intermediate used in the synthesis of a protein kinase C inhibitor drug through a combination of hetero-Diels-Alder and biocatalytic reactions. The Diels-Alder reaction between ethyl glyoxylate and butadiene was used to make racemic 2-ethoxycarbonyl-3,6-dihydro-2H-pyran. Treatment of the racemic ester with Bacillus lentus protease resulted in the selective hydrolysis of the (R)-enantiomer and yielded (S)-2-ethoxycarbonyl-3,6-dihydro-2H-pyran in excellent optical purity, which was reduced to (S)-3,6-dihydro-2H-pyran-2-yl methanol. Tritylation of this alcohol, followed by reductive ozonolysis and mesylation afforded the product in 10-15% overall yield with excellent optical and chemical purity. Details of the process development work done on each step are given. 

The second portion of this chapter describes the process development of nevirapine, a novel nonnucleoside reverse transcriptase (NNRT) inhibitor used in the treatment of AIDS. This case study details the evolution of the nevirapine process from conception in medicinal chemistry through process development, pilot plant scale-up, and commercial launch of the bulk active drug substance. Restricting the case study to nevirapine allows the process and rationale to be described in more detail. The authors are aware of the vast amount of excellent process development that has been performed in the commercialization of other drug products. The processes described herein are not necessarily a unique solution to this particular synthesis. To some extent, they reflect the culture, philosophy, raw materials, equipment, and synthetic tools available during this period of time (1990-1996) as well as the initiatives of the process chemists. 

The final example of a novel process development formulation involves a semi-solid ophthalmic gel containing a carbonic anhydrase inhibitor drug for the treatment of glaucoma. It is administered to the patient by extruding the gel from an ophthalmic tube into the conjunctival sac of the eye. The drug had a very low aqueous solubility. It was necessary to reduce the particle size of the drug to less than 10 pim and suspend it in a very thick carbomer gel vehicle, to increase the residence time of the gel and maximise corneal permeation. The formulation details are given below ... 

In the next contribution we learn about hands-on experience and recent improvements with different production systems for biopharmaceuticals at Bayer Health-Care. As previously also published in Nature by Heiner Apeler, Head of Expression, an E. coli host/vector system was originally developed for the efficient production of an interleukin-4 variant, but afterwards it was optimized for the expression of other proteins and even Fab fragments. Process development and optimization of the yeast secretory Saccharomyces cerevisiae for expression of a protease inhibitor will also be presented. The focus, however, is on the use of a recently developed mammalian HKBll (hybrid clone of human kidney and B cells) expression system for recombinant human glycoprotein biopharmaceuticals. HKBll is a favorable cell host for the production of human proteins, because it dehvers biopharmaceuticals that are structurally identical to the natural product. The host/vector system supports the production of gram quantities of proteins in a large-scale transient transfection format as well as the development of stable cell fines. These systems together... 

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