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Atazanavir, sold under the brand name Reyataz among others, is an antiretroviral medication used to treat HIV/AIDS. The combination atazanavir/ritonavir is on the World Health Organization's List of Essential Medicines. Atazanavir is available as a generic medication.
Medical uses
thumb|Two Reyataz 200 mg capsules
Atazanavir is used in the treatment of HIV. The efficacy of atazanavir has been assessed in a number of well-designed trials in ART-naive and ART-experienced adults.
Atazanavir is distinguished from other protease inhibitors in that it has lesser effects on lipid profile and appears to be less likely to cause lipodystrophy. There may be some cross-resistant with other protease inhibitors. It was not associated with any birth defects among over 2,500 live births observed. Atazanavir resulted in a better cholesterol profile and confirmed that it is a safe option during pregnancy.
Atazanavir inhibits the enzyme UDP glucuronosyltransferase (UGT) 1A1, thereby impacting the hepatic glucuronidation and elimination of bilirubin. As such atazanavir may not be prescribed to patients with UGT1A1 deficiencies (e.g. those who suffer from Gilbert's syndrome or Crigler–Najjar syndrome) in order to avoid the possibility of jaundice. If the HIV protease enzyme does not work, the virus is not infectious, and no mature virions are made.
The azapeptide drug was designed as an analog of the peptide chain substrate that HIV protease would cleave normally into active viral proteins. More specifically, atazanavir is a structural analog of the transition state during which the bond between a phenylalanine and proline is broken. Humans do not have any enzymes that break bonds between phenylalanine and proline, so this drug will not target human enzymes.
Synthesis
A couple of atazanavir syntheses were originally reported. Below is one of them.
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The condensation of p-bromobenzaldehyde [1122-91-4] (1) with methanol gives 4-bromobenzaldehyde dimethyl acetal [24856-58-4] (2). Grignard reaction with the reagent from 2-bromopyridine [109-04-6] causes a coupling exactly like in the Ullmann reaction. The product from this step is called 2-(4-dimethoxymethylphenyl)pyridine [1033125-49-3]. After the hydrolysis of the acetal, the product is called 4-(2-pyridyl)benzaldehyde [127406-56-8] (3). Condensation with tert-Butyl carbazate [127406-56-8] to form the respective hydrazone (PC29940792); reduction of the azo FG gives the hydrazine [198904-85-7] (4). This reaction with (2S,3S)-1,2-Epoxy-3-(Boc-amino)-4-phenylbutane [98737-29-2] (5) led to PC98076738 (6). Removal of both the Boc protecting groups with acid gives the penultimate compound, i.e. (2R,3S)-3-amino-1-[amino-[(4-pyridin-2-ylphenyl)methyl]amino]-4-phenylbutan-2-ol, PC98008965 (7). The last step requires a double amide formation with 2 equivalents of methyl N-[(2S)-1-chloro-3,3-dimethyl-1-oxobutan-2-yl]carbamate (8). This completes the synthesis of atazanavir (9).