(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl N-[(2S,3R)-3-hydroxy-4-[N-(2-methylpropyl)4-aminobenzenesulfonamido]-1-phenylbutan-2-yl]carbamate

• ChemBase ID: 1132
• Molecular Formular: C27H37N3O7S
• Molecular Mass: 547.66358
• Monoisotopic Mass: 547.23522154
• SMILES: S(=O)(=O)(N(C[C@@H](O)[C@@H](NC(=O)O[C@@H]1[C@H]2[C@@H](OC1)OCC2)Cc1ccccc1)CC(C)C)c1ccc(N)cc1
• Canonical SMILES: CC(CN(S(=O)(=O)c1ccc(cc1)N)C[C@H]([C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@@H]2[C@H]1CCO2)O)C
• InChI: InChI=1S/C27H37N3O7S/c1-18(2)15-30(38(33,34)21-10-8-20(28)9-11-21)16-24(31)23(14-19-6-4-3-5-7-19)29-27(32)37-25-17-36-26-22(25)12-13-35-26/h3-11,18,22-26,31H,12-17,28H2,1-2H3,(H,29,32)/t22-,23-,24+,25-,26+/m0/s1
• InChIKey: CJBJHOAVZSMMDJ-HEXNFIEUSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl N-[(2S,3R)-3-hydroxy-4-[N-(2-methylpropyl)4-aminobenzenesulfonamido]-1-phenylbutan-2-yl]carbamate
• IUPAC Traditional name: (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl N-[(2S,3R)-3-hydroxy-4-[N-(2-methylpropyl)4-aminobenzenesulfonamido]-1-phenylbutan-2-yl]carbamate; darunavir
• Brand Name: Prezista
• Synonyms: Darunavirum [INN-latin]; TMC-114; UIC-94017; AIDS073035; TMC114; Darunavir; [(1S,2R)-3-[[(4-Aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenyl-methyl)propyl]carabamic Acid (3R,3aS,6aR)-Hexahydrofuro[2,3-b]-furan-3-yl Ester

Database IDs

• CAS Number: 206361-99-1
• PubChem SID: 46506908; 160964595
• PubChem CID: 213039

CALCULATED PROPERTIES

JChem

• Acid pKa: 13.588299
• H Acceptors: 7
• H Donor: 3
• LogD (pH = 5.5): 2.8164854
• LogD (pH = 7.4): 2.8168132
• Log P: 2.8168175
• Molar Refractivity: 142.3406 cm^3
• Polarizability: 56.468124 Å^3
• Polar Surface Area: 140.42 Å^2
• Rotatable Bonds: 11
• Lipinski's Rule of Five: false

ALOGPS 2.1

• Log P: 1.76
• LOG S: -3.91
• Solubility (Water): 6.68e-02 g/l

PROPERTIES

Physical Property

• Solubility: Approximately 0.15 mg/mL at 20°C as ethanolate salt; Chloroform; Methanol
• Apperance: Off-White to Pale Yellow Solid
• Melting Point: 130-132°C
• Hydrophobicity(logP): 1.8

Safety Information

• Storage Condition: -20°C Freezer

DETAILS

DrugBank - DB01264

• Drug Groups: approved
• Description: Darunavir is a protease inhibitor used to treat HIV. It acts on the HIV aspartyl protease which the virus needs to cleave the HIV polyprotein into its functional fragments.
• Indication: Darunavir, co-administered with ritonavir, and with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV) infection in antiretroviral treatment-experienced adult patients, such as those with HIV-1 strains resistant to more than one protease inhibitor.
• Pharmacology: Darunavir is an inhibitor of the human immunodeficiency virus (HIV) protease. In studies, the drug, co-administered with ritonavir in combination therapy, significantly reduced viral load and increased CD4 cell counts in this treatment-experienced patient population (Tibotec, 2006, Product Monograph, Prezista 2006). Darunavir is used as an adjunct therapy with low dose ritonavir, which inhibits cytochrome P450 3A (CYP3A) which increases the bioavailability and half life of darunavir.
• Affected Organisms: Human Immunodeficiency Virus
• Biotransformation: Hepatic. Darunavir is extensively metabolized by CYP enzymes, primarily by CYP3A.
• Absorption: The absolute oral bioavailability of a single 600 mg dose of darunavir alone and after co-administration with 100 mg ritonavir twice daily was 37% and 82%, respectively.
• Half Life: The terminal elimination half-life of darunavir was approximately 15 hours when combined with ritonavir.
• Protein Binding: Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma alpha 1-acid glycoprotein (AAG).
• Elimination: Darunavir is primarily metabolized by CYP3A. Darunavir is extensively metabolized by CYP enzymes, primarily by CYP3A. A mass balance study in healthy volunteers showed that after single dose administration of 400 mg 14C-darunavir, co-administered with 100 mg ritonavir, approximately 79.5% and 13.9% of the administered dose of 14C-darunavir was recovered in the feces and urine, respectively.
• Clearance: * 32.8 L/hr [Healthy volunteers receiving intravenous administration of 400 mg of darunavir]; * 5.9 L/hr [Healthy volunteers receiving intravenous administrations of 400 mg of darunavir and 100 mg of ritonavir twice daily]
• References: Back D, Sekar V, Hoetelmans RM: Darunavir: pharmacokinetics and drug interactions. Antivir Ther. 2008;13(1):1-13. [Pubmed] ; Medilexicon [Link] ; Company Website [Link] ; Tremblay CL: Combating HIV resistance - focus on darunavir. Ther Clin Risk Manag. 2008 Aug;4(4):759-66. [Pubmed] ; Koh Y, Matsumi S, Das D, Amano M, Davis DA, Li J, Leschenko S, Baldridge A, Shioda T, Yarchoan R, Ghosh AK, Mitsuya H: Potent inhibition of HIV-1 replication by novel non-peptidyl small molecule inhibitors of protease dimerization. J Biol Chem. 2007 Sep 28;282(39):28709-20. Epub 2007 Jul 17. [Pubmed] ; Kovalevsky AY, Tie Y, Liu F, Boross PI, Wang YF, Leshchenko S, Ghosh AK, Harrison RW, Weber IT: Effectiveness of nonpeptide clinical inhibitor TMC-114 on HIV-1 protease with highly drug resistant mutations D30N, I50V, and L90M. J Med Chem. 2006 Feb 23;49(4):1379-87. [Pubmed] ; De Meyer S, Azijn H, Surleraux D, Jochmans D, Tahri A, Pauwels R, Wigerinck P, de Bethune MP: TMC114, a novel human immunodeficiency virus type 1 protease inhibitor active against protease inhibitor-resistant viruses, including a broad range of clinical isolates. Antimicrob Agents Chemother. 2005 Jun;49(6):2314-21. [Pubmed]
• External Links: Wikipedia; RxList; Drugs.com

Toronto Research Chemicals - D193500

Second generation HIV-1-protease inhibitor; structurally similar to amprenavir. Antiviral.

REFERENCES

• Back D, Sekar V, Hoetelmans RM: Darunavir: pharmacokinetics and drug interactions. Antivir Ther. 2008;13(1):1-13. Pubmed
• Tremblay CL: Combating HIV resistance - focus on darunavir. Ther Clin Risk Manag. 2008 Aug;4(4):759-66. Pubmed
• Koh Y, Matsumi S, Das D, Amano M, Davis DA, Li J, Leschenko S, Baldridge A, Shioda T, Yarchoan R, Ghosh AK, Mitsuya H: Potent inhibition of HIV-1 replication by novel non-peptidyl small molecule inhibitors of protease dimerization. J Biol Chem. 2007 Sep 28;282(39):28709-20. Epub 2007 Jul 17. Pubmed
• Kovalevsky AY, Tie Y, Liu F, Boross PI, Wang YF, Leshchenko S, Ghosh AK, Harrison RW, Weber IT: Effectiveness of nonpeptide clinical inhibitor TMC-114 on HIV-1 protease with highly drug resistant mutations D30N, I50V, and L90M. J Med Chem. 2006 Feb 23;49(4):1379-87. Pubmed
• De Meyer S, Azijn H, Surleraux D, Jochmans D, Tahri A, Pauwels R, Wigerinck P, de Bethune MP: TMC114, a novel human immunodeficiency virus type 1 protease inhibitor active against protease inhibitor-resistant viruses, including a broad range of clinical isolates. Antimicrob Agents Chemother. 2005 Jun;49(6):2314-21. Pubmed
• Company Website Link
• Medilexicon Link
• Koh, Y., et al.: Antimicrob. Agents Chemother., 47, 3123 (2003)
• Arasteh, K., et al.: AIDS, 19, 943 (2003)
• Surleraux, D.L.N.G., et al.: J. Med. Chem., 48, 1813 (2003)