Statins Protease inhibitors

Specific concomitant medications or consumptions (check specific statin package insert for warnings) fibrates (especially gemfibrozil, but other fibrates too), nicotinic acid (rarely), cyclosporine, azole antifungals such as itraconazole and ketoconazole, macrolide antibiotics such as erythromycin and clarithromycin, protease inhibitors used to treat Acquired Immune Deficiency Syndrome, nefazodone (antidepressant), verapamil, amiodarone, large quantities of grapefruit juice (usually more than 1 quart per day), and alcohol abuse (independently predisposes to myopathy)... 

A third dataset was built in order to demonstrate that the descriptor is relevant for estimating binding affinity in a QSAR analysis. This last dataset contains 49 HIV-1 protease inhibitors, the 3D coordinates of which were those used by Pastor et al. (30). It has the four transition-state isosteres—hydroxy ethylene, hydroxyethylamine, statine, and a symmetrical diol. The X-ray structures of molecules numbered 1 and 3-34 have been reported (31), whereas molecules numbered 35-50 were modeled on the crystallographic structure of the complex of HIV-1 protease with L-689,502 solved at 2.25 A resolution (32). The binding affinity is expressed as pIC50 values. 

These aspartic protease inhibitors are also "lead compounds" in the development of inhibitors of HIV protease. As in statine-based inhibitors, the site of occupancy by the catalytic H20 (green in Eq. 12-23) is occupied in the inhibitor by something that mimics a tetrahedral intermediate with - CHOH -P02H etc.bb Tremendous efforts are being expended in designing these inhibitors and considerable... 

The intense interest in y - am i n o - (i -hydroxy acid related peptides has led to a great deal of effort devoted to their synthesis. Statine analogues Ahppa (11), Achpa (12), and Dahoa (13) (Scheme 2), which correspond to the replacement of the chain equivalent of leucine in statine by those of phenylalanine, cyclohexylalanine, and lysine, respectively, were used to synthesize inhibitors of pepsin, renin, and penicillinopepsinJ1314] With the objective of developing highly specific inhibitors, C2-substituted analogues have also been introduced into short, substrate-derived inhibitors, e.g. the a,a-difluoro statine 14 in renin inhibitors,1151 and N -substituted statine derivatives like 15 in HIV-1 protease inhibitors.[16]... 

Structural studies of complexes between aspartyl proteases and statine-based inhibitors indicate that the hydroxy group of statine displaces a water molecule present at the active site, and forms hydrogen bonds with the two aspartic carbonyl groups which are essential to the mechanism of hydrolysis. 2 The replacement of this hydroxy moiety by an amine (Scheme 19) has been investigated in order to increase the binding strength by electrostatic interac-... 

Healthy volunteers were given protease inhibitors and statins, and the authors concluded that simvastatin should be avoided and that atorvastatin could be used with caution in people taking ritonavir and saquinavir (111). Dosage adjustment of pravastatin may be necessary with co-administration of ritonavir and saquinavir. Pravastatin does not alter the pharmacokinetics of nelfinavir, and thus appears to be safe for co-administration. 

According to Rich, new protease inhibitors were produced by replacing statine in pepstatin derivatives with (3S,4S)-4,8-diamino-3-hydroxyoctanecarboxylic acid (DAHOA) 85 a 189a) or 4-amino-3-hydroxy-5-phenylpentanecarboxylic acid (AHPPA) 85b 189b-c>. 

PROTEASE INHIBITORS LIPID-LOWERING DRUGS- STATINS ... 

PROTEASE INHIBITORS LOVASTATIN, SIMVASTATIN T risk of adverse effects Inhibition of CYP3A4-mediated metabolism of these statins Avoid co-administration... 

Figure 7 Various transition-state protease inhibitors. Bortezomib is an approved drug for the treatment of multiple myeloma. It is a boronic acid analog that inhibits the proteosome, a threonine protease. The boronic acid moiety can adopt a tetrahedral conformation in the active site. Pepstatin is a peptidyl aspartic acid inhibitor. The reactive statine group binds to the catalytic machinery, and the chiral hydroxyl group of the statine mimics the tetrahedral geometry of the transition state. Idinavir is an approved HIV 1 Protease inhibitor that binds to the active site via a hydroxyethylene transition state isostere. Aldehydes are also transition state analogs, which are susceptible to nucleophilic attack. In cysteine, serine and threonine proteases, this results in a covalent, reversible inhibition mechanism.

More recently, the principles for designing inhibitors of aspartic proteases have been applied to the design of inhibitors of j8-secretase (BACEor Memapsin-2)as potential agents for treating or preventing Alzheimer s disease (95, 96). Both statine-derived inhibitors (43) and hydro3 ethylene-derived BACE inhibitors have been reported (Fig. 15.21)07,98). A crystal structure of (44) bound to j3-secretase has been reported (99). As expected, the hy-... 

Statins are well absorbed after administration orally, and are metabolised in the liver. They are well tolerated, the commonest adverse effect being transient, and usually minor abnormality of liver function tests in some 1% of patients. Asymptomatic elevation of muscle enzymes (creatine phos-phokinase, CPK) and myositis (with a generalised muscle discomfort) occur more rarely, but is more frequent when statins are combined with other anti-hyperlidaemic drugs such as fibrates and nicotinic acid patients should be counseled about myositis when these drugs are co-administered. Myositis is also more likely with co-administered anti-HIV protease inhibitors, and with drugs that interfere with metabolism of some statins, e.g. ciclosporin. 

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