Ketoconazole structure

There are six crystal structures reported in the Protein Data Bank two without ligand (ltqnand IwOe), one cocrystallized with progesterone (7) (IwOf), one with mytrapone (8) (IwOg), one with ketoconazole (9) (2j0c) and one with erythromycin (10) (2j0d). 

A4 Midazolam, Testosterone (strongly recommended to use at least two structurally unrelated substrates) Nifedipine, Felodipine, Cyclosporine, Terfenadine, Erythromycin, Simvastatin Ketoconazole (recent evidence that it is also a potent inhibitor of 2C8), Troleandomycin Cyclosporine... 

The starting dataset used to develop the 3D quantitative structure property relationship (3D-QSPR) model consisted of 370 commercially available compounds. Activity data and 2D structures were retrieved from the Cerep database [18]. Inhibition of CYP 3A4 was reported as inhibition of the formation of 6y9-hydroxy-tes-tosterone [19]. Ketoconazole was used as reference compound so that all values are expressed as percentages. The log of the normalized CYP3A4 inhibition per-... 

Fig. 4.3 Structures of polyene (amphotericin B) and azole (itraconazole, fluconazole, miconazole and ketoconazole) antifungal agents.

Fig-1 Structures of naringenin (flavanone, 1), naringin (flavanone O-glycoside, 2) and rutin (flavonol O-glycoside, 3), ketoconazole (4), 7/3-hydroxycholesterol (5) and 25-hydroxycholesterol (6), resveratrol (7) and etoposide (8, VP-16)... 

Very recently two new ligand bound CYP3A4 structures were reported, one with the inhibitor ketoconazole (22) and the second with the substrate erythromycin [45], Unlike the metyrapone case, both of these structures dis-... 

Figure 17.11 Ligands found in the various CYP3A4 crystal structures (a) Metyra-pone with the classic direct coordination to the heme iron, (b) progesterone sitting at the mouth of the entrance channel, (c) two molecules of ketoconazole sitting in a highly distorted active site, and (d) erythromycin sitting close to the heme but in the wrong orientation for metabolism.

Itraconazole. Itraconazole (18) is a highly lipophilic compound with a triazole structure. Compared to ketoconazole, itraconazole has a broader spectrum (including Aspergillus spp.) (29,30) and an in vitro activity that is 10 times higher than ketoconazole for most species. 

Terconazole and butoconazole Terconazole is a ketal triazole with structural similarities to ketoconazole. The mechanism of action of terconazole is similar to that of the imidazoles. The 80-mg vaginal suppository is inserted at bedtime for 3 days, whereas the 0.4% vaginal cream is used for 7 days, and the 0.8% cream for 3 days. Clinical efficacy and patient acceptance of both preparations are at least as good as for clotrimazole in patients with vaginal candidiasis. Butoconazole is an imidazole that is pharmacologically quite comparable to clotrimazole. 

Figure 10.2 The reversible CYP3A4 inhibitor and antifungal drug ketoconazole, the irreversible CYP3 A4 inhibitor and proestrogen drug gestodene, and the quasi-irreversible CYP3A4 inhibitor and antibacterial drug erythromycin. Structural features key to their CYP inhibition are shown in blue.

The CYP450 3A4 model based on the ketoconazole crystal structure was used within MetaSite3 to predict SOM for compound 4 (Figure 11.5a). Built-in corrections for reactivity of the cytochrome and the ligand were applied. Both for compounds 3 and 4, the predicted primary SOM is the benzylic alpha position to the thiadiazole ring (Figure 11.5b). The SOM predicted by MetaSite next in hierarchy, the hydroxylation of the benzylic position of the cyclohexyl moiety, was not observed experimentally, nor was the aromatic oxidation of the benzothiazole sulfur. Instead, in vitro metabolism studies are in agreement with the primary SOM and confirmed a labile cyclopentyl-ethyl moiety, but a stable thiadiazol scaffold and a stable... 

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