Crixivan

FIGURE 16.29 (left) HIV-1 protease com-plexed with the inhibitor Crixivan (red) made by Merck. The flaps (residues 46-55 from each snbnnit) covering the active site are shown in green and the active site aspartate residues involved in catalysis are shown in white. 

Crixivan 400-mg caps IDV 800 mg + RTV 100 bid IDV 800 mg + RTV 200 mg bid insufficiency due to cirrhosis 600 mg q8hours Take 1 hour before or 2 hours after heavy meals, or concomitantly with low-fat meal No restrictions when used with RTV nausea indirect hyperbilirubinemia hyperlipidemia headache, asthenia, blurred vision, dizziness, rash, metallic taste, thrombocytopenia, alopecia, hemolytic anemia hyperglycemia fat maldistribution increased bleeding episodes in patients with hemophilia (less than RTV)... 

Crixivan, a drug produced by Merck and Co. (the world s premier drug firm, 1 billion annual research spending), is widely used in the fight against AIDS (acquired immune deficiency syndrome). 

Crixivan inhibits an enzyme called HIV (human immunodeficiency virus) protease. 

Crixivan interacts in a highly specific way with the three-dimensional structure of HIV protease. 

A critical requirement for this interaction is the hydroxyl (OH) group near the center of Crixivan. This hydroxyl group of Crixivan mimics the true chemical intermediate that forms when HIV protease performs its task in the AIDS virus. 

By having a higher affinity for the enzyme than its natural reactant, Crixivan ties... 

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). 

DIPAMP-Rh complex to give the corresponding chiral a-amino acid derivative in over 98% ee. The chiral product has been used for the synthesis of (S)-(-)-ac-romelobic acid [88]. Hydrogenation of a tetrahydropyrazine derivative catalyzed by a PHANEPHOS-Rh complex at -40"C gives an intermediate for the synthesis of Crixivan in 86% ee [82a]. Hydrogenation of another tetrahydropyrazine carboxamide derivative catalyzed by an (R)-BINAP-Rh catalyst leads to the chiral product in 99% ee [89]. 

In some circumstances, the FDA processes drug reviews under the accelerated scheme. This mechanism is to review and approve drugs speedily for cases where effective therapies are lacking or in situations of rare diseases. One of the fastest approval times to date is the case of imatinib mesylate (Gleevec, Novartis—Exhibit 7.3) for the treatment of chronic myeloid leukemia (CML) it was approved in less than 3 months after the filing of an NDA with the FDA. Another example is the new AIDS drug indinavir (Crixivan, Merck), which was approved in a mere 42 days. 

Recently, the Merck Research Laboratory demonstrated an important example." Initially the HIV protease inhibitor Crixivan (MK 639) 29 (Scheme 1.10) could not be prepared very well by a complicated conventional multistep synthesis, but 29 became available when it was prepared by an easier synthesis, whose essential step was accomplished by a U-4CR. 

Imipenem (Primaxin) Indapamide (Lozol) Indinavir (Crixivan)... 

Hulme C, Gore V (2003) Multi-component reactions emerging chemistry in drug discover. From xylocain to crixivan. Curr Med Chem 10 51-80... 

This procedure can be used to synthesize the key intermediate 34 of Merck s HIV protease inhibitor Crixivan 35 (Fig. 5) [25]. This reaction is done using dichloroacetaldehyde 26 instead of chloroacetaldehyde, forming the classical Ugi product 30. This intermediate is then treated with triethylamine to obtain the corresponding vinylchloride 31. Cyclization with KO Bu followed by stereoselective hydrogenation using the chiral catalyst Rh-BINAP afforded the Crixivan intermediate 34. (Scheme 5) The classical way to make this intermediate requires five steps, and thus makes the MCR route more attractive [25]. 

Fig. 5 HIV protease inhibitor Crixivan 35 (yellow) bound to HIV protease (grey) [24]. The piperazine moiety of Crixivan comprises scaffolding as well binding qualities as depicted by the piperazine hydrogen bonds (PDB ID ISDU)...

Scheme 5 Asymmetric MCR synthesis to piperazine intermediate (34) of the Merck HIV protease inhibitor Crixivan (BINAP 2,2 -bis(diphenylphosphino)-1,10-binaphthyl COD cyclo-octadiene)...

Indinavir (Crixivan) is a potent inhibitor of HIV reverse transcriptase. It produces the side effects common to aU protease inhibitors and also may produce nephrolithiasis, urolithiasis, and possibly renal insufficiency or renal failure. This problem occurs more fre-... 

Crixivan (Indinavir Sulfate) , Physicians Desk Reference, 51 Edition, Medical Economics Company, Inc., Montvale, NJ, 1997, pp. 1670-1673. 

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