Identification

Name
Calanolide A
Accession Number
DB04886
Type
Small Molecule
Groups
Investigational
Description

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.

Structure
Thumb
Synonyms
  • (+)-calanolide A
  • (+/-)-calanolide A
Categories
UNII
S5A9TQN46W
CAS number
142632-32-4
Weight
Average: 370.4388
Monoisotopic: 370.178023942
Chemical Formula
C22H26O5
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[[email protected]@H](O)[[email protected]](C)[[email protected]@H](C)O1

Pharmacology

Indication

For use in combination treatment of HIV infection (AIDS).

Structured Indications
Not Available
Pharmacodynamics

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.

TargetActionsOrganism
UGag-Pol polyproteinNot AvailableHIV-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
Toxicity
Not Available
Affected organisms
  • Human Immunodeficiency Virus
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

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
KEGG Compound
C09147
PubChem Compound
64972
PubChem Substance
175426889
ChemSpider
58497
BindingDB
50002662
ChEBI
65552
ChEMBL
CHEMBL267447

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections1
1Unknown StatusTreatmentHuman Immunodeficiency Virus (HIV) Infections1

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
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 RuleNoChemAxon
MDDR-like RuleNoChemAxon
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
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
Angular pyranocoumarin / Pyranochromene / 2,2-dimethyl-1-benzopyran / Chromane / Benzopyran / 1-benzopyran / Alkyl aryl ether / Pyranone / Benzenoid / Pyran
show 12 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
organic heterotetracyclic compound, secondary alcohol, delta-lactone, cyclic ether (CHEBI:65552) / coumarins (C09147)

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 spher...
Gene Name
gag-pol
Uniprot ID
P03369
Uniprot Name
Gag-Pol polyprotein
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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
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]

Drug created on October 21, 2007 06:30 / Updated on November 09, 2017 03:48