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Crixivan: Capsule: 400 mg/1: Oral: ..

Harvesting short-lived hypoiodous acid for efficient diastereoselective iodohydroxylation in Crixivan® synthesis

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Strecker amino acid synthesis - Wikipedia

The required dose of Merck's protease inhibitor Crixivan, for example, was 2.4 g per day—almost a kilogram per patient per year. "We were afraid that if we ever ran out, we would be dooming the patients," says Paul J. Reider. Now vice president of chemistry research and discovery at Amgen, Reider led the team at Merck Research Laboratories tha t developed the process chemistry route to Crixivan. ' We needed unbelievably high amounts of the most complex product we'd ever made by chemical synthesis," Reider says. "Our success or failure would result in people living or dying."

block piperazine 17 in the synthesis of the HIV protease inhibitor Crixivan®.

Toluene dioxygenase (TDO) from Pseudomonas putida F1 converts indene to a mixture of cis-indandiol (racemic), 1-indenol, and 1-indanone. The desired product, cis-(1S, 2R)-indandiol, is a potential key intermediate in the chemical synthesis of indinavir sulfate (Crixivan), Merck's HIV-1 protease inhibitor for the treatment of AIDS. To reduce the undesirable byproducts 1-indenol and 1-indanone formed during indene bioconversion, the recombinant TDO expressed in Escherichia coli was evolved by directed evolution using the error-prone polymerase chain reaction (epPCR) method. High-throughput fluorometric and spectrophotometric assays were developed for rapid screening of the mutant libraries in a 96-well format. Mutants with reduced 1-indenol by-product formation were identified, and the individual indene bioconversion product profiles of the selected mutants were confirmed by HPLC. Changes in the amino acid sequence of the mutant enzymes were identified by analyzing the nucleotide sequence of the genes. A mutant with the most desirable product profile from each library, defined as the most reduced 1-indenol concentration and with the highest cis-(1S, 2R)-indandiol enantiomeric excess, was used to perform each subsequent round of mutagenesis. After three rounds of mutagenesis and screening, mutant 1C4-3G was identified to have a threefold reduction in 1-indenol formation over the wild type (20% vs 60% of total products) and a 40% increase of product (cis-indandiol) yield.

An efficient asymmetric hydrogenation approach to …

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Crixivan wasn't Merck's first protease inhibitor candidate, Volante notes. In working on the initial compound, Vblante's team devised a synthetic strategy for putting a basic framework in place. The strategy was fed back to the medicinal chemists, who used it to make variations on the core structure.

Crixivan ™ is one of the most effective treatments now available for AIDS therapy. However, the drug’s costly and difficult chemical synthesis has led the search for alternative pathways of synthesis. Specifically, researchers sought to eliminate several of the steps involved in the drug’s chemical synthesis by employing bacteria strains capable of producing certain key components of the synthesis. It has been shown that Rhodococcus I24 can convert indene to indandiol, a key ingredient in the Crixivan ™ synthesis. Furthermore, a naphthalene-inducible dioxgenase (nidAB) system has been identified in Rhodococcus I24. Naphthalene is an aromatic compound similar to indene. Our goal is to gain a better understanding of the mechanism of regulation of the nidAB system in Rhodococcus I24. The naphthalene-inducible dioxgenase of Rhodococcus I24, encoded by nidAB genes, can convert indene into cis-(1R, 2S)-indandiol. Using Northern blot analysis, we studied the regulation by naphthalene on the expression of the nidAB genes. By reporter gene strategy, we examined the role of naphthalene on a 800bp segment of the upstream sequence of nidAB at the transcriptional level. The upstream sequence from nidAB was cloned into a promoterless lacZ cassette. Results from Northern blot analysis suggest little change of nidAB gene expression in the presence of naphthalene. ß-galactosidase assays suggest no naphthalene-induced transcriptional regulation by the upstream sequence from nidAB operon. Continued study of the naphthalene-responsiveness and regulation of nidAB genes will provide a better understanding of this dioxygenase system and indene bioconversion in Rhodococcus I24.

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Read "ChemInform Abstract: An Efficient Asymmetric Hydrogenation Approach to the Synthesis of the Crixivan ® Piperazine Intermediate., ChemInform" on DeepDyve…

The desired product, cis -(1S, 2R)-indandiol, is a potential key intermediate in the chemical synthesis of indinavir sulfate (Crixivan), Merck's HIV-1 protease inhibitor for the treatment of AIDS.

Fill in missing compounds and reagents in the following outline of a hypothetical synthesis of the acyclic central portion of Crixivan. Note that more than one intermediate compound may be involved between some of the structures shown below.

Keywords: HIV Protease Inhibitor, Enzymatic Synthesis, biotransformation, Crixivan, Aminoacylation, Paclitaxel, Orally Active Taxane
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  • Is 'HIV' Really the Cause of AIDS

    The two problems below are directed toward devising some hypothetical pathways for the synthesis of Crixivan.

  • XHTML namespace - World Wide Web Consortium

    Ph Cl N Cl HN NH O t BuNH TsO O Crixivan Fragment Syntheses Epoxide TsO O HO 1 from CHEM 221 at Emory

  • Crixivan - Chemical & Engineering News

    Click the structures and reaction arrows in sequence to view the 3D models and animations respectively

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Livro Organic Chemistry - J. Clayden - 2a edição - …

As bumpy as the road to success may have been at times, the history-making team effort that helped create Crixivan still evokes fond memories among its members.

Looking back over his 25 years with the company, Vacca - who is still with Merck and currently serves as the company's executive director of medicinal chemistry - says the Crixivan era was the most thrilling and rewarding.

"We were working on an important disease that at the time had no treatment options," said Vacca, adding that it was very exciting to see the clinical data come out from the trials that showed how powerful protease inhibitors were compared to nucleoside analogues.

Meanwhile, patent co-author Katharine Holloway calls herself a "virtual chemist." Her role in the process was to model proposed HIV protease inhibitors in order to help prioritise those which were most interesting for synthesis. Holloway modelled a novel inhibitor template based on an idea developed by Vacca, and demonstrated its potential for further work.

The team knew that HIV could rapidly develop resistance to any single therapy, and so from the very beginning HIV protease inhibitors were taken in a "cocktail" with other antiretroviral drugs as part of HAART (Highly Active AntiRetroviral Therapy).

History and the Discovery and Development of Crixivan

N2 - Toluene dioxygenase (TDO) from Pseudomonas putida F1 converts indene to a mixture of cis-indandiol (racemic), 1-indenol, and 1-indanone. The desired product, cis-(1S, 2R)-indandiol, is a potential key intermediate in the chemical synthesis of indinavir sulfate (Crixivan), Merck's HIV-1 protease inhibitor for the treatment of AIDS. To reduce the undesirable byproducts 1-indenol and 1-indanone formed during indene bioconversion, the recombinant TDO expressed in Escherichia coli was evolved by directed evolution using the error-prone polymerase chain reaction (epPCR) method. High-throughput fluorometric and spectrophotometric assays were developed for rapid screening of the mutant libraries in a 96-well format. Mutants with reduced 1-indenol by-product formation were identified, and the individual indene bioconversion product profiles of the selected mutants were confirmed by HPLC. Changes in the amino acid sequence of the mutant enzymes were identified by analyzing the nucleotide sequence of the genes. A mutant with the most desirable product profile from each library, defined as the most reduced 1-indenol concentration and with the highest cis-(1S, 2R)-indandiol enantiomeric excess, was used to perform each subsequent round of mutagenesis. After three rounds of mutagenesis and screening, mutant 1C4-3G was identified to have a threefold reduction in 1-indenol formation over the wild type (20% vs 60% of total products) and a 40% increase of product (cis-indandiol) yield.

CiteSeerX — Naphthalene-Responsiveness and …

Even the company responsible for the patent, Merck Inc., admits that the road to the drug's ultimate success was filled with setbacks - not least the death of original project leader Irving Sigal, who passed away in 1988.

But despite this tragedy and numerous other difficulties along the way, it took just four years from first synthesis to the approved drug reaching the market, something of a miracle in this often slow-moving industry.

Vacca, an American, was one of the two group leaders on the HIV protease project trying out different design ideas. One of the compound series credited to Vacca was the combination of a piece from the clinical compound created at Hoffman LaRoche (LaRoche's drug eventually became Saquinavir) with part of a compound that his own group had developed three years earlier.

The first example of this combination series was created by James Guare, and showed some weak activity. Vacca then made the key compound in the series. It was this compound that - after so many disappointments - gave the team hope that they could find an optimal solution.

Another team member, Bruce Dorsey, took over this series from Vacca and eventually arrived at the compound that later became Crixivan and went on to generate substantial market success for Merck Inc., including $294 million revenue in 2002 alone.

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