Atazanavir

Base Information

• Chemical Name: Atazanavir
• CAS No.: 198904-31-3
• Molecular Formula: C38H52N6O7
• Molecular Weight: 704.867
• European Community (EC) Number: 812-543-8
• UNII: QZU4H47A3S
• DSSTox Substance ID: DTXSID9048691
• Nikkaji Number: J1.006.724C
• Wikipedia: Atazanavir
• Wikidata: Q423467
• NCI Thesaurus Code: C66872
• RXCUI: 343047
• Pharos Ligand ID: RLRCXU4Q7NCC
• Metabolomics Workbench ID: 43308
• ChEMBL ID: CHEMBL1163
• Mol file: 198904-31-3.mol

Synonyms:232632, BMS;3,12-bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-((4-(2-pyridinyl)phenyl)methyl)-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester;atazanavir;atazanavir sulfate;BMS 232632;BMS 232632 05;BMS-232632;BMS-232632-05;BMS232632;BMS23263205;CGP 73547;CGP 75136;CGP 75176;CGP 75355;CGP-73547;CGP-75136;CGP-75176;CGP-75355;CGP73547;CGP75136;CGP75176;CGP75355;Reyataz

Chemical Property of Atazanavir

Chemical Property:

• Appearance/Colour: crystalline solid
• Melting Point: 207-209 °C
• Refractive Index: 1.562
• PKA: 11.11±0.46(Predicted)
• PSA: 171.22000
• Density: 1.178 g/cm³
• LogP: 5.77520
• Storage Temp.: -20°C Freezer
• Solubility.: Ethanol (Slightly), Methanol (Slightly)
• XLogP3: 5.6
• Hydrogen Bond Donor Count: 5
• Hydrogen Bond Acceptor Count: 9
• Rotatable Bond Count: 18
• Exact Mass: 704.38974802
• Heavy Atom Count: 51
• Complexity: 1110

Purity/Quality:

99% ^*data from raw suppliers

Atazanavir ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Canonical SMILES: CC(C)(C)C(C(=O)NC(CC1=CC=CC=C1)C(CN(CC2=CC=C(C=C2)C3=CC=CC=N3)NC(=O)C(C(C)(C)C)NC(=O)OC)O)NC(=O)OC
• Isomeric SMILES: CC(C)(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)[C@H](CN(CC2=CC=C(C=C2)C3=CC=CC=N3)NC(=O)[C@H](C(C)(C)C)NC(=O)OC)O)NC(=O)OC
• Recent ClinicalTrials: Extension Study for Patients Who Had Not Met Criteria for Discontinuation in Previous Sponsored Belinostat Trials
• Recent EU Clinical Trials: A Phase 3 Randomized, Active-Controlled, Open-Label Clinical Study to Evaluate a Switch to Doravirine/Islatravir (DOR/ISL) Once-Daily in Participants With HIV-1 Virologically Suppressed on Antiretroviral Therapy
• Recent NIPH Clinical Trials: A Randomized, Open Label, Multicenter Study Comparing the Safety and Efficacy of Once Daily Regimen Containing Epzicom or Truvada Combined with Ritonavir Boosted Atazanavir as Initial Therapy for HIV-1 Infection
• Description: Atazanavir is an inhibitor of human immunodeficiency virus type 1 (HIV-1) protease, an enzyme that is essential for the processing of Gag and Gag-Pol polyproteins into structural and enzymatic proteins required for viral replication. It has a similar pharmacophore motif to the other six widely marketed HIV protease inhibitors, most of which are based upon a hydroxyethylamine template. Uniquely, it possesses an aza-peptide motif but maintains many similar pharmacophore elements including lipophilic moieties that presumably bind to S2, S1, S′1 , and S′2 positions. Atazanavir is pseudo-symmetric about the central template, incorporating D-tert-Leucine at both termini. This compound is synthesized in about seven steps, with a key coupling of the chiral epoxide (derived from phenylalanine and imparting one chiral center) and N-tert-boc-N′-(4-[2-pyridyl]benzyl)hydrazine. Removal of both tert-Boc groups and double acylation with methoxycarbonyl-tert-Leucine provides the product. Another synthesis of atazanavir entails ten steps and utilizes α-(tert-bocamino) phenylpropanal as a chiral intermediate. It is a potent inhibitor of indinavir-resistant and saquinavir-resistant strains of HIV-1 (IC50=0.03–0.1 and 0.04–0.1 μM, respectively). In 300 patients who had failed previous treatment, atazanavir (400 mg once daily) was compared to lopinavir (400 mg twice daily) and ritonavir (100 mg); both arms additionally receiving two non-reverse transcriptase inhibitors. After 24 weeks, HIV RNA levels of ＜400 copies/mL were noted in 61% of patients receiving atazanavir and 81% of those taking lopinavir/ritonavir. After 96 weeks of therapy with atazanavir, HIV RNA copy levels were found to be ＜400 and ＜50 in 80 and 58% of patients, respectively. A study of the cross-resistance profile relative to other protease inhibitors using a panel of 551 clinical isolates (without prior atazanavir exposure but with cross-resistance to one or two other protease inhibitors; the majority had resistance to nelfinavir) showed that greater than 80% retained susceptibility to atazanavir. All of the resistant isolates from patients taking atazanavir had an I50 L substitution. The recommended dosage of atazanavir is 400 mg once daily. It has a mean half-life range of 7.9–6.5 h with about 60% bioavailability and moderate plasma protein binding (86% albumin and 89% alpha-1- acid glycoprotein (AAG)). Atazanavir was well tolerated in clinical studies and it displayed minimal lipid modulation when tested in combination with two non-reverse transcriptase inhibitors. Atazanavir had no effect on total cholesterol, low-density lipoprotein, and triglyceride levels when compared with other protease inhibitors that caused sustained elevations in these lipid levels.
• Uses: Atazanavir is a novel azapeptide protease inhibitor (PI) Atazanavir is a novel azapeptide HIV protease inhibitor (PI). Antiviral. Atazanavir is an inhibitor of HIV-1 protease (EC50 = 2.6 nM). In isolated cells, it has additive to moderately synergistic antiviral effects when combined with other antiretroviral drugs. As a result, it is commonly used in vivo in combination therapy for HIV-1 infection. Atazanavir competitively inhibits UDP-gluronosyltransferase, which conjugates bilirubin for clearance, leading to hyperbilirubinemia in a significant portion of those receiving atazanavir therapy.
• Clinical Use: Treatment of HIV infection (in combination with other antiretroviral drugs)
• Drug interactions: Potentially hazardous interactions with other drugs Anti-arrhythmics: possibly increased levels of amiodarone and lidocaine. Antibacterials: concentration of both drugs increased when given with clarithromycin; rifabutin concentration increased - reduce dose of rifabutin; rifampicin reduces atazanavir concentration - avoid; avoid with telithromycin in severe renal and hepatic impairment. Anticoagulants: avoid with apixaban and rivaroxaban. Antidepressants: concentration reduced by St John’s wort - avoid. Antifungals: concentration increased by posaconazole; concentration of voriconazole increased or decreased, concentration of atazanavir also reduced. Antimalarials: avoid with artemether/lumefantrine; may increase quinine concentration. Antipsychotics: possibly inhibits metabolism of aripiprazole - reduce dose of aripiprazole; possibly increased concentration of pimozide and quetiapine - avoid. Antivirals: concentration reduced by boceprevir; concentration of daclatasvir increased, reduce dose of daclatasvir; absorption reduced by didanosine tablets; concentration reduced by efavirenz - avoid; concentration of elvitegravir increased when atazanavir boosted with ritonavir - reduce elvitegravir dose; concentration possibly reduced by nevirapine - avoid; concentration of paritaprevir increased; increased risk of ventricular arrhythmias with saquinavir - avoid; concentration reduced by tenofovir and tenofovir concentration possibly increased; avoid with indinavir; concentration of maraviroc increased, consider reducing dose of maraviroc; possibly reduces telaprevir concentration, also concentration of atazanavir increased; concentration of tipranavir increased, also concentration of atazanavir reduced; avoid with elbasvir/grazoprevir, increased grazoprevir concentration. Anxiolytics and hypnotics: possibly increases concentration of midazolam - avoid with oral midazolam. Calcium-channel blockers: concentration of diltiazem increased - reduce dose of diltiazem; possibly increased verapamil concentration. Ciclosporin: possibly increased concentration of ciclosporin. Colchicine: possibly increases risk of colchicine toxicity, avoid in hepatic or renal impairment. Cytotoxics: possibly increases concentration of axitinib, reduce dose of axitinib; possibly increases concentration of bosutinib, avoid or reduce dose; possibly increases concentration of crizotinib and everolimus - avoid; avoid with cabazitaxel and pazopanib; concentration of ibrutinib possibly increased, reduce dose of ibrutinib; possibly inhibits metabolism of irinotecan - increased risk of toxicity. Dapoxetine: avoid concomitant use, increased risk of toxicity. Ergot alkaloids: possibly increased concentration of ergot alkaloids - avoid. Orlistat: absorption possibly reduced by orlistat. Ranolazine: possibly increases ranolazine concentration - avoid. Sildenafil: possibly increased side effects of sildenafil. Sirolimus: possibly increased concentration of sirolimus. Statins: avoid with simvastatin - increased risk of myopathy; possibly increased risk of myopathy with atorvastatin, pravastatin and rosuvastatin - reduce rosuvastatin dose. Tacrolimus: possibly increased concentration of tacrolimus. Ticagrelor: possibly increases concentration of ticagrelor - avoid. Ulcer-healing drugs: concentration significantly reduced by omeprazole and esomeprazole and possibly other proton pump inhibitors - avoid; concentration possibly reduced by histamine H2 antagonists.

Technology Process of Atazanavir

There total 61 articles about Atazanavir which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 100.0%

C14H18N4O4 (869285-68-7) + 1-[4-(pyridin-2-yl)phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-phenyl-2-azahexane trihydrochloride (198904-87-9) → atazanavir (198904-31-3,1292296-09-3)

Guidance literature:

With dipotassium hydrogenphosphate; In water; at 5 - 40 ℃;

Reference yield: 95.0%

C14H18N4O4 (869285-68-7) + 1-[4-(Pyridin-2-yl)phenyl]-5(S)-2,5-bis[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-azahexane.3hydrochloride → atazanavir (198904-31-3,1292296-09-3)

Guidance literature:

With dipotassium hydrogenphosphate; In water; at 5 - 40 ℃; for 1.5 - 2h;

Reference yield: 95.0%

{(S)-1-[N'-((2S,3S)-3-amino-2-hydroxy-4-phenyl-butyl)-N'-(4-pyridin-2-yl-benzyl)-hydrazinocarbonyl]-2,2-dimethyl-propyl}-carbamic acid methyl ester (857900-54-0) + (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid (162537-11-3) → atazanavir (198904-31-3,1292296-09-3)

Guidance literature:

With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane;

DOI:10.1002/jlcr.1019

upstream raw materials:

(S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid

1-[4-(pyridin-2-yl)phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-phenyl-2-azahexane trihydrochloride

{(S)-1-[N'-((2S,3S)-3-amino-2-hydroxy-4-phenyl-butyl)-N'-(4-pyridin-2-yl-benzyl)-hydrazinocarbonyl]-2,2-dimethyl-propyl}-carbamic acid methyl ester

1-(4-(pyridin-2-yl)benzyl)hydrazine

Refernces

• 1、 -. "Method for synthesis of atazanavir". Paragraph 0049; 0050; 0052. . Retrieved 2018/04/01.
• 2、 -. "Method for preparing anti-AIDS drug-Atazanavir monomer". Paragraph 0022; 0023; 0024; 0025. . Retrieved 2017/06/02.