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Identification
NameCalanolide A
Accession NumberDB04886
TypeSmall Molecule
GroupsInvestigational
DescriptionCalanolide 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.
Structure
Thumb
Synonyms
(+)-calanolide A
(+/-)-calanolide A
External Identifiers Not Available
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIS5A9TQN46W
CAS number142632-32-4
WeightAverage: 370.4388
Monoisotopic: 370.178023942
Chemical FormulaC22H26O5
InChI KeyNIDRYBLTWYFCFV-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)[[email protected]](C)[C@@H](C)O1
Pharmacology
IndicationFor use in combination treatment of HIV infection (AIDS).
Structured Indications Not Available
PharmacodynamicsCalanolide 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 actionViral 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.
TargetKindPharmacological actionActionsOrganismUniProt ID
Gag-Pol polyproteinProteinunknownNot AvailableHIV-1P03369 details
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Hepatic.

Route of eliminationNot Available
Half life20 hours for 800mg
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Human Immunodeficiency Virus
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available
References
Synthesis ReferenceNot Available
General References
  1. 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. [PubMed:12501127 ]
  2. 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. [PubMed:14980631 ]
  3. 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. [PubMed:15074925 ]
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Clinical Trials
Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections1
1CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections1
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.0178 mg/mLALOGPS
logP4.18ALOGPS
logP3.79ChemAxon
logS-4.3ALOGPS
pKa (Strongest Acidic)13.63ChemAxon
pKa (Strongest Basic)-3.4ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area64.99 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity104.11 m3·mol-1ChemAxon
Polarizability40.99 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9901
Blood Brain Barrier+0.8789
Caco-2 permeable+0.7886
P-glycoprotein substrateSubstrate0.6977
P-glycoprotein inhibitor INon-inhibitor0.5696
P-glycoprotein inhibitor IINon-inhibitor0.521
Renal organic cation transporterNon-inhibitor0.9172
CYP450 2C9 substrateNon-substrate0.7451
CYP450 2D6 substrateNon-substrate0.847
CYP450 3A4 substrateSubstrate0.5905
CYP450 1A2 substrateNon-inhibitor0.7102
CYP450 2C9 inhibitorInhibitor0.5
CYP450 2D6 inhibitorNon-inhibitor0.8947
CYP450 2C19 inhibitorNon-inhibitor0.7118
CYP450 3A4 inhibitorNon-inhibitor0.7872
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7001
Ames testNon AMES toxic0.6246
CarcinogenicityNon-carcinogens0.9035
BiodegradationNot ready biodegradable0.9889
Rat acute toxicity2.7417 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9428
hERG inhibition (predictor II)Non-inhibitor0.9579
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
Taxonomy
DescriptionThis compound belongs to the class of chemical entities known as angular pyranocoumarins. These are organic compounds containing a pyran (or a hydrogenated derivative) angularly fused to a coumarin moiety.
KingdomChemical entities
Super ClassOrganic compounds
ClassPhenylpropanoids and polyketides
Sub ClassCoumarins and derivatives
Direct ParentAngular pyranocoumarins
Alternative Parents
Substituents
  • Angular pyranocoumarin
  • Pyranochromene
  • 2,2-dimethyl-1-benzopyran
  • Chromane
  • Benzopyran
  • 1-benzopyran
  • Alkyl aryl ether
  • Pyranone
  • Benzenoid
  • Pyran
  • Heteroaromatic compound
  • Lactone
  • Secondary alcohol
  • Ether
  • Oxacycle
  • Organoheterocyclic compound
  • Alcohol
  • Hydrocarbon derivative
  • Organic oxide
  • Organic oxygen compound
  • Organooxygen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors

Targets

Kind
Protein
Organism
HIV-1
Pharmacological action
unknown
General Function:
Zinc ion binding
Specific Function:
Gag-Pol polyprotein: Mediates, with Gag polyrotein, 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...
Gene Name:
gag-pol
Uniprot ID:
P03369
Molecular Weight:
162014.15 Da
References
  1. Hanna L: Calanolide A: a natural non-nucleoside reverse transcriptase inhibitor. BETA. 1999 Apr;12(2):8-9. [PubMed:11366704 ]
  2. 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. [PubMed:12501127 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. Egger J: Psychoneurological aspects of food allergy. Eur J Clin Nutr. 1991;45 Suppl 1:35-45. [PubMed:1855506 ]
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Drug created on October 21, 2007 06:30 / Updated on August 17, 2016 12:24