Explore a selection of our essential drug information below, or:
Identification
- Generic Name
- Calanolide A
- DrugBank Accession Number
- DB04886
- Background
Calanolide A is a new non-nucleoside reverse transcriptase inhibitor (NNRTI) derived from a plant found in the Malaysian rain forest. A related compound, calanolide B, also has anti-HIV activity. Both drugs are being developed by Sarawak Pharmaceuticals. A preliminary dosing study among HIV-infected individuals showed a significant antiviral effect compared with placebo.
- Type
- Small Molecule
- Groups
- Investigational
- Structure
Structure for Calanolide A (DB04886)
- Weight
- Average: 370.4388
Monoisotopic: 370.178023942 - Chemical Formula
- C22H26O5
- Synonyms
- (+)-calanolide A
Pharmacology
- Indication
For use in combination treatment of HIV infection (AIDS).
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Calanolide A is a new non-nucleoside reverse transcriptase inhibitor (NNRTI) derived from a plant found in the Malaysian rain forest. A related compound, calanolide B, also has anti-HIV activity. Both drugs are being developed by Sarawak Pharmaceuticals. The drug is metabolised by cytochrome P450 CYP3A, and its developers have suggested that drug levels may be enhanced if co-administered with ritonavir (Norvir). The drug is active in the test tube against HIV with the two most common NNRTI-related mutations, K103N and Y181C, and selects for a mutation which does not cause cross-resistance with any other NNRTIs currently under investigation. A substitution at codon Y188H of reverse transcriptase has been associated with 30-fold resistance to calanolide A in vitro (Quan 1999). The compound is essentially inactive against strains of the less common HIV type 2.
- Mechanism of action
Viral life-cycle studies indicate that calanolide A acts early in the infection process, similar to the known HIV reverse transcriptase (RT) inhibitor 2', 3'-dideoxycytidine. In enzyme inhibition assays, calanolide A potently and selectively inhibits recombinant HIV type 1 RT but not cellular DNA polymerases or HIV type 2 RT within the concentration range tested.
Target Actions Organism AGag-Pol polyprotein inhibitorUGag-Pol polyprotein Not Available HIV-1 - Absorption
Not Available
- Volume of distribution
Not Available
- Protein binding
Not Available
- Metabolism
Hepatic.
- Route of elimination
Not Available
- Half-life
20 hours for 800mg
- Clearance
Not Available
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
Not Available
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAcetohexamide The therapeutic efficacy of Acetohexamide can be increased when used in combination with Calanolide A. Adenovirus type 7 vaccine live The therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Calanolide A. Anthrax vaccine The therapeutic efficacy of Anthrax vaccine can be decreased when used in combination with Calanolide A. Bacillus calmette-guerin substrain connaught live antigen The therapeutic efficacy of Bacillus calmette-guerin substrain connaught live antigen can be decreased when used in combination with Calanolide A. Bacillus calmette-guerin substrain russian BCG-I live antigen The therapeutic efficacy of Bacillus calmette-guerin substrain russian BCG-I live antigen can be decreased when used in combination with Calanolide A. - Food Interactions
- Not Available
Categories
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as angular pyranocoumarins. These are organic compounds containing a pyran (or a hydrogenated derivative) angularly fused to a coumarin moiety.
- Kingdom
- Organic compounds
- Super Class
- Phenylpropanoids and polyketides
- Class
- Coumarins and derivatives
- Sub Class
- Pyranocoumarins
- Direct Parent
- Angular pyranocoumarins
- Alternative Parents
- Pyranochromenes / 2,2-dimethyl-1-benzopyrans / Pyranones and derivatives / Alkyl aryl ethers / Benzenoids / Heteroaromatic compounds / Secondary alcohols / Lactones / Oxacyclic compounds / Organic oxides show 1 more
- Substituents
- 1-benzopyran / 2,2-dimethyl-1-benzopyran / Alcohol / Alkyl aryl ether / Angular pyranocoumarin / Aromatic heteropolycyclic compound / Benzenoid / Benzopyran / Chromane / Ether show 12 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- organic heterotetracyclic compound, secondary alcohol, delta-lactone, cyclic ether (CHEBI:65552) / coumarins (C09147)
- Affected organisms
- Human Immunodeficiency Virus
Chemical Identifiers
- UNII
- S5A9TQN46W
- CAS number
- 142632-32-4
- InChI Key
- NIDRYBLTWYFCFV-FMTVUPSXSA-N
- InChI
- InChI=1S/C22H26O5/c1-6-7-13-10-15(23)26-21-16(13)20-14(8-9-22(4,5)27-20)19-17(21)18(24)11(2)12(3)25-19/h8-12,18,24H,6-7H2,1-5H3/t11-,12-,18+/m1/s1
- IUPAC Name
- (10R,11S,12S)-12-hydroxy-6,6,10,11-tetramethyl-4-propyl-6,10,11,12-tetrahydro-2H-1,5,9-trioxatriphenylen-2-one
- SMILES
- CCCC1=CC(=O)OC2=C1C1=C(C=CC(C)(C)O1)C1=C2[C@@H](O)[C@H](C)[C@@H](C)O1
References
- General References
- Eiznhamer DA, Creagh T, Ruckle JL, Tolbert DT, Giltner J, Dutta B, Flavin MT, Jenta T, Xu ZQ: Safety and pharmacokinetic profile of multiple escalating doses of (+)-calanolide A, a naturally occurring nonnucleoside reverse transcriptase inhibitor, in healthy HIV-negative volunteers. HIV Clin Trials. 2002 Nov-Dec;3(6):435-50. [Article]
- Xu ZQ, Barrow WW, Suling WJ, Westbrook L, Barrow E, Lin YM, Flavin MT: Anti-HIV natural product (+)-calanolide A is active against both drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis. Bioorg Med Chem. 2004 Mar 1;12(5):1199-207. [Article]
- Sekino E, Kumamoto T, Tanaka T, Ikeda T, Ishikawa T: Concise synthesis of anti-HIV-1 active (+)-inophyllum B and (+)-calanolide A by application of (-)-quinine-catalyzed intramolecular oxo-Michael addition. J Org Chem. 2004 Apr 16;69(8):2760-7. [Article]
- External Links
- KEGG Compound
- C09147
- PubChem Compound
- 64972
- PubChem Substance
- 175426889
- ChemSpider
- 58497
- BindingDB
- 50002662
- ChEBI
- 65552
- ChEMBL
- CHEMBL267447
- ZINC
- ZINC000001645454
- Wikipedia
- Calanolide_A
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample data1 Completed Treatment Human Immunodeficiency Virus (HIV) Infections 1 somestatus stop reason just information to hide 1 Unknown Status Treatment Human Immunodeficiency Virus (HIV) Infections 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
- Not Available
- Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0178 mg/mL ALOGPS logP 4.18 ALOGPS logP 3.79 Chemaxon logS -4.3 ALOGPS pKa (Strongest Acidic) 13.63 Chemaxon pKa (Strongest Basic) -3.4 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 64.99 Å2 Chemaxon Rotatable Bond Count 2 Chemaxon Refractivity 104.11 m3·mol-1 Chemaxon Polarizability 41 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.9901 Blood Brain Barrier + 0.8789 Caco-2 permeable + 0.7886 P-glycoprotein substrate Substrate 0.6977 P-glycoprotein inhibitor I Non-inhibitor 0.5696 P-glycoprotein inhibitor II Non-inhibitor 0.521 Renal organic cation transporter Non-inhibitor 0.9172 CYP450 2C9 substrate Non-substrate 0.7451 CYP450 2D6 substrate Non-substrate 0.847 CYP450 3A4 substrate Substrate 0.5905 CYP450 1A2 substrate Non-inhibitor 0.7102 CYP450 2C9 inhibitor Inhibitor 0.5 CYP450 2D6 inhibitor Non-inhibitor 0.8947 CYP450 2C19 inhibitor Non-inhibitor 0.7118 CYP450 3A4 inhibitor Non-inhibitor 0.7872 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.7001 Ames test Non AMES toxic 0.6246 Carcinogenicity Non-carcinogens 0.9035 Biodegradation Not ready biodegradable 0.9889 Rat acute toxicity 2.7417 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9428 hERG inhibition (predictor II) Non-inhibitor 0.9579
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-00di-0009000000-752ed0e113942e91aa8c Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-014i-0009000000-a67d1ed90ddad2c3b6c2 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-016r-0009000000-9569316b8ddae1be718e Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-00di-0009000000-6c0ec9baa0cb9f105986 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0fb9-0029000000-08d7835259bdf95747ce Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0ufs-0039000000-acabfb48a83f244af657 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 202.5620567 predictedDarkChem Lite v0.1.0 [M-H]- 191.53519 predictedDeepCCS 1.0 (2019) [M+H]+ 202.5810567 predictedDarkChem Lite v0.1.0 [M+H]+ 193.93074 predictedDeepCCS 1.0 (2019) [M+Na]+ 202.8410567 predictedDarkChem Lite v0.1.0 [M+Na]+ 199.99294 predictedDeepCCS 1.0 (2019)
Targets
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- Kind
- Protein
- Organism
- Not Available
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Gag-Pol polyprotein Mediates, with Gag polyprotein, the essential events in virion assembly, including binding the plasma membrane, making the protein-protein interactions necessary to create spherical particles, recruiting the viral Env proteins, and packaging the genomic RNA via direct interactions with the RNA packaging sequence (Psi). Gag-Pol polyprotein may regulate its own translation, by the binding genomic RNA in the 5'-UTR. At low concentration, the polyprotein would promote translation, whereas at high concentration, the polyprotein would encapsidate genomic RNA and then shut off translation.
- Specific Function
- aspartic-type endopeptidase activity
- Gene Name
- gag-pol
- Uniprot ID
- P03366
- Uniprot Name
- Gag-Pol polyprotein
- Molecular Weight
- 163287.51 Da
References
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- Kind
- Protein
- Organism
- HIV-1
- Pharmacological action
- Unknown
- General Function
- Gag-Pol polyprotein Mediates, with Gag polyprotein, the essential events in virion assembly, including binding the plasma membrane, making the protein-protein interactions necessary to create spherical particles, recruiting the viral Env proteins, and packaging the genomic RNA via direct interactions with the RNA packaging sequence (Psi). Gag-Pol polyprotein may regulate its own translation, by the binding genomic RNA in the 5'-UTR. At low concentration, the polyprotein would promote translation, whereas at high concentration, the polyprotein would encapsidate genomic RNA and then shut off translation.
- Specific Function
- aspartic-type endopeptidase activity
- Gene Name
- gag-pol
- Uniprot ID
- P03369
- Uniprot Name
- Gag-Pol polyprotein
- Molecular Weight
- 162014.15 Da
References
- Hanna L: Calanolide A: a natural non-nucleoside reverse transcriptase inhibitor. BETA. 1999 Apr;12(2):8-9. [Article]
- Eiznhamer DA, Creagh T, Ruckle JL, Tolbert DT, Giltner J, Dutta B, Flavin MT, Jenta T, Xu ZQ: Safety and pharmacokinetic profile of multiple escalating doses of (+)-calanolide A, a naturally occurring nonnucleoside reverse transcriptase inhibitor, in healthy HIV-negative volunteers. HIV Clin Trials. 2002 Nov-Dec;3(6):435-50. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
- Specific Function
- 1,8-cineole 2-exo-monooxygenase activity
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Wu X, Zhang Q, Guo J, Jia Y, Zhang Z, Zhao M, Yang Y, Wang B, Hu J, Sheng L, Li Y: Metabolism of F18, a Derivative of Calanolide A, in Human Liver Microsomes and Cytosol. Front Pharmacol. 2017 Jul 19;8:479. doi: 10.3389/fphar.2017.00479. eCollection 2017. [Article]
Drug created at October 21, 2007 12:30 / Updated at August 26, 2024 19:22