Protease inhibitors indinavir

The incorporation of an ionizable center, such as an amine or similar function, into a template can bring a number of benefits, including water solubility. A key step in the discovery of the protease inhibitor, indinavir was the incorporation of a basic amine (and a pyridine) into the backbone of hydroxyethylene transition state mimic compounds L-685,434 to enhance solubility (and potency) (Fig. 1.2) [17]. 

In people who take the protease inhibitor indinavir, the herb St. John s wort reduces the concentration of indinavir in the blood. A similar interaction has been reported between St. John s wort and the heart medication digoxin. 

Enantiomerically pure epoxides and diols, readily available through the asymmetric epoxidation and asymmetric dihydroxylation reactions, are ideal precursors to prepare cis-amino alcohols via the Ritter reaction. " " A Merck group has shown that indene oxide 175a can be converted effectively to c/i-l-amino-2-indanol, a key fragment of the HlV-protease inhibitor Indinavir via the cis-... 

During an investigatior of the utihty of epoxide 240 as an intermediate in the synthesis of the HIV protease inhibitor Indinavir 241, it was found that the amino alcohol 237 must first be protected prior to iodination. Without protection, the iodination of the unsaturated amide 237 gave the unstable oxazoline 239 in 83% yield (Scheme 8.65). 

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.

Koudriakova T, latsimirskaia E, Utkin I, et al. Metabolism of the human immunodeficiency virus protease inhibitors indinavir and ritonavir by human intestinal microsomes and expressed cytochrome P4503A4/3A5 mechanism-based inactivation of cytochrome P4503A by ritonavir. Drug Metab Dispos 1998 26(6) 552-561. 

If St. John s wort can alter levels of cyclosporin in the blood, might it not also interfere with the action of other medications Recent research indicates that it can. Not surprisingly, the affected drugs are those that, like cyclosporin, are also metabolized by cytochrome enzymes. Protease inhibitors, used in the treatment of hiv infections, are a prime example. Because of the popularity of St. John s wort as an antidepressant and the incidence of depression in patients diagnosed with HIV infections, researchers at the U.S. National Institutes of Health decided to investigate the consequences of using the herbal remedy and the protease inhibitor indinavir concurrently. Doctors prescribe indinavir to prevent the hiv virus... 

The effects of the protease inhibitor indinavir and the NNRTI efavirenz on lipid concentrations have been compared in a large comparative randomized study (154). Each of the two comparison drugs were used in one arm (with a zidovudine + lamivudine backbone) and the combination of the two drugs in a third arm. Zidovudine and lamivudine did not play a role in the lipid changes. However, both of the comparison drugs significantly increased cholesterol concentrations. 

One of the few industrial examples of the asymmetric synthesis of halohydrins is in a process to the human immunodeficiency virus (HIV) protease inhibitor, Indinavir.190 The y,8-unsaturated carboxamide 23 is smoothly converted into iodohydrin 24 (92%, 94% de) (Scheme 9.34). (For more on the chemistry of the indanol, see Chapter 24.)191... 

ALMOTRIPTAN, ELETRIPTAN PROTEASE INHIBITORS -INDINAVIR, NELFINAVIR, RITONAVIR Possibly t adverse effects when almotriptan or eletriptan is coadministered with indinavir, ritonavir (with or without lopinavir), or nelfinavir Inhibition of CYP3A4- and possibly CYP2D6-mediated metabolism of eletriptan, and CYP3A4-mediated metabolism of almotriptan Avoid co-administration... 

CANNABIS ANTIVIRALS-PROTEASE INHIBITORS-indinavir, nelfinavir, nevirapine, ritonavir, saquinavir Cannabis may cause l plasma concentrations of protease inhibitors, particularly indinavir and nelfinavir Cannabis may cause inhibition or induction of CYP3A4 isoenzymes, which metabolize these protease inhibitors Be aware. Regular monitoring of viral indicators is necessary... 

Dieleman IP, in t Veld B, Borleffs JC, Schreij G. Acute respiratory failure associated with the human immunodeficiency virus (HIV) protease inhibitor indinavir in an HIV-infected patient. Clin Infect Dis I998 26(4) 1012-13. 

Hermieu J, Prevot M, Ravery V, Sauty L, Moulinier F, Delmas V, Bouvet E, Boccon-Gibod L. Urohthiasis and the protease inhibitor indinavir. Eur Urol 1999 35(3) 239-41. 

It seems very likely that the protease inhibitor indinavir inhibited the metabolism of phenylpropanolamine by cytochrome P450 (predominantly CYP3A4), increasing circulating concentrations, and causing systemic and cerebral vasoconstriction. 

The use of rifampicin with the protease inhibitors indinavir, nelfinavir, and amprenavir is contraindicated. However, these agents can be used with rifabutin after appropriate dosage reduction. Failure to reduce the dosage of rifabutin can result in toxic manifestations, such arthralgia and uveitis. 

Dieleman JP, Sturkenboom MC, Jambroes M, Gyssens 1C, Weverling GJ, ten Veen JH, Schrey G, Reiss P, Strieker BH Athena Study Group. Risk factors for urological symptoms in a cohort of users of the HIV protease inhibitor indinavir sulfate the ATHENA cohort. Arch Intern Med 2002 162 1493-501. 

HIV protease inhibitors Indinavir Ritonavir Saquinavir Prokinetic ... 

HIV protease inhibitors Indinavir Nelfinavir Ritonavir Saquinavir Amiodarone not Azithromycin Cimetidme Clarithromycin . Diltiazem Erythromycin Fluoxetine Fluvoxamine Grapefruit Juice Itraconazole Ketoconazole Mibefradil Nefezodone Troleandomydn Verapamil... 

L. Pang, W. Hsieh, J. Braun, M.P. Gatto, G.J. Matuszewski, B.K. "High-Throughput Simultaneous Determination of the HIV Protease Inhibitors Indinavir and L-756423 in Human Plasma Using Semi-Automated 96-Well Solid Phase Extraction and LC-MS/MS, J. Pharm. Biomed. Anal. 24(2), 291-305 (2000). 

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