Identification

Name
Pimecrolimus
Accession Number
DB00337  (APRD01182)
Type
Small Molecule
Groups
Approved, Investigational
Description

Pimecrolimus is an immunomodulating agent used in the treatment of atopic dermatitis (eczema). It is currently available as a topical cream, once marketed by Novartis, (however Galderma will be promoting the molecule in Canada in early 2007) under the trade name Elidel. [Wikipedia]

Structure
Thumb
Synonyms
  • 33-Epi-chloro-33-desoxyascomycin
  • Pimecrolimus
  • Pimecrolimusum
External IDs
ASM 981 / SDZ ASM 981 / SDZ ASM-981
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ElidelCream10 mg/1gTopicalValeant Pharmaceuticals North America2001-12-02Not applicableUs
ElidelCream1 %TopicalValeant Canada Lp Valeant Canada S.E.C.2003-03-24Not applicableCanada
ElidelCream10 mg/1gTopicalValeant Pharmaceuticals North America2001-12-02Not applicableUs
ElidelCream10 mg/1gTopicalNovartis2001-12-022013-04-30Us
ElidelCream10 mg/1gTopicalValeant Pharmaceuticals North America2001-12-02Not applicableUs
ElidelCream10 mg/1gTopicalPhysicians Total Care, Inc.2003-10-30Not applicableUs
ElidelCream10 mg/1gTopicalValeant Pharmaceuticals North America2001-12-02Not applicableUs
International/Other Brands
Aregen (Meda Pharm) / Rizan (Esteve)
Categories
UNII
7KYV510875
CAS number
137071-32-0
Weight
Average: 810.46
Monoisotopic: 809.4480897
Chemical Formula
C43H68ClNO11
InChI Key
KASDHRXLYQOAKZ-XDSKOBMDSA-N
InChI
InChI=1S/C43H68ClNO11/c1-10-30-18-24(2)17-25(3)19-36(53-8)39-37(54-9)21-27(5)43(51,56-39)40(48)41(49)45-16-12-11-13-32(45)42(50)55-38(28(6)33(46)23-34(30)47)26(4)20-29-14-15-31(44)35(22-29)52-7/h18,20,25,27-33,35-39,46,51H,10-17,19,21-23H2,1-9H3/b24-18+,26-20+/t25-,27+,28+,29-,30+,31-,32-,33-,35+,36-,37-,38+,39+,43+/m0/s1
IUPAC Name
(1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-[(1E)-1-[(1R,3R,4S)-4-chloro-3-methoxycyclohexyl]prop-1-en-2-yl]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,⁹]octacos-18-ene-2,3,10,16-tetrone
SMILES
[H][C@]1(CC[C@H](Cl)[C@@H](C1)OC)\C=C(/C)[C@@]1([H])OC(=O)[C@]2([H])CCCCN2C(=O)C(=O)[C@]2(O)O[C@@]([H])([C@H](C[C@H]2C)OC)[C@H](C[C@@H](C)C\C(C)=C\[C@@H](CC)C(=O)C[C@H](O)[C@H]1C)OC

Pharmacology

Indication

For treatment of mild to moderate atopic dermatitis.

Associated Conditions
Pharmacodynamics

Pimecrolimus is a chemical that is used to treat atopic dermatitis (eczema). Atopic dermatitis is a skin condition characterized by redness, itching, scaling and inflammation of the skin. The cause of atopic dermatitis is not known; however, scientists believe that it may be due to activation of the immune system by various environmental or emotional triggers. Scientists do not know exactly how pimecrolimus reduces the manifestations of atopic dermatitis, but pimecrolimus reduces the action of T-cells and mast cells which are part of the immune system and contribute to responses of the immune system. Pimecrolimus prevents the activation of T-cells by blocking the effects of chemicals (cytokines) released by the body that stimulate T-cells. Pimecrolimus also reduces the ability of mast cells to release chemicals that promote inflammation.

Mechanism of action

Pimecrolimus binds with high affinity to macrophilin-12 (FKBP-12) and inhibits the calcium-dependent phosphatase, calcineurin. As a consequence, it inhibits T cell activation by blocking the transcription of early cytokines. In particular, pimecrolimus inhibits at nanomolar concentrations Interleukin-2 and interferon gamma (Th1-type) and Interleukin-4 and Interleukin-10 (Th2-type) cytokine synthesis in human T cells. Also, pimecrolimus prevents the release of inflammatory cytokines and mediators from mast cells in vitro after stimulation by antigen/lgE.

TargetActionsOrganism
ASerine/threonine-protein kinase mTOR
potentiator
Human
UPeptidyl-prolyl cis-trans isomerase FKBP1A
potentiator
Human
Absorption

Because of the low systemic absorption of pimecrolimus following topical application the calculation of standard pharmacokinetic measures such as AUC, Cmax, half-life, etc. cannot be reliably done.

Volume of distribution
Not Available
Protein binding

74%-87% (in vitro, bound to plasma proteins)

Metabolism

No drug metabolism was observed in human skin in vitro. Oral administration yielded metabolites produced from O-demethylation and oxygenation reactions.

Route of elimination

80% of the drug is excreted in the feces.

Half life
Not Available
Clearance
Not Available
Toxicity

Side effects include burning sensation, irritation, pruritus, erythema, and skin infections, at the application site.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe serum concentration of (R)-warfarin can be increased when it is combined with Pimecrolimus.
(S)-WarfarinThe serum concentration of (S)-Warfarin can be increased when it is combined with Pimecrolimus.
16-BromoepiandrosteroneThe metabolism of 16-Bromoepiandrosterone can be decreased when combined with Pimecrolimus.
2-MethoxyethanolThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with 2-Methoxyethanol.
3-isobutyl-1-methyl-7H-xanthineThe metabolism of 3-isobutyl-1-methyl-7H-xanthine can be decreased when combined with Pimecrolimus.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Pimecrolimus.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Pimecrolimus.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Pimecrolimus.
6-Deoxyerythronolide BThe metabolism of Pimecrolimus can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Pimecrolimus.
Food Interactions
Not Available

References

Synthesis Reference

Viktor Gyollai, Csaba Szabo, "Methods of preparing pimecrolimus." U.S. Patent US20060142564, issued June 29, 2006.

US20060142564
General References
  1. Grassberger M, Baumruker T, Enz A, Hiestand P, Hultsch T, Kalthoff F, Schuler W, Schulz M, Werner FJ, Winiski A, Wolff B, Zenke G: A novel anti-inflammatory drug, SDZ ASM 981, for the treatment of skin diseases: in vitro pharmacology. Br J Dermatol. 1999 Aug;141(2):264-73. [PubMed:10468798]
External Links
PubChem Compound
6509979
PubChem Substance
46505748
ChemSpider
21111755
ChEBI
135888
ChEMBL
CHEMBL1200686
Therapeutic Targets Database
DAP000594
PharmGKB
PA164783790
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Pimecrolimus
ATC Codes
D11AH02 — Pimecrolimus
AHFS Codes
  • 84:92.00 — Misc. Skin and Mucous Membrane Agents
FDA label
Download (230 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableAtopic Dermatitis (AD)1
1CompletedTreatmentAtopic Dermatitis (AD)1
1CompletedTreatmentHealthy Volunteers1
1, 2CompletedTreatmentNetherton Syndrome1
2CompletedTreatmentAtopic Dermatitis (AD)3
2CompletedTreatmentLichen Sclerosus et Atrophicus1
2CompletedTreatmentOral Lichen Planus1
2CompletedTreatmentPrurigo Nodularis1
2CompletedTreatmentSeborrheic Dermatitis1
2TerminatedTreatmentOral Erosive Lichen Planus1
2Unknown StatusSupportive CareRash1
3CompletedTreatmentAtopic Dermatitis (AD)7
3CompletedTreatmentChronic Hand Dermatitis1
3CompletedTreatmentLichen Planus, Oral1
3CompletedTreatmentPerioral Dermatitis1
4CompletedTreatmentAtopic Dermatitis (AD)18
4CompletedTreatmentMild to Moderate Atopic Dermatitis1
4CompletedTreatmentOral Lichen Planus1
4RecruitingTreatmentAtopic Dermatitis (AD)1
4TerminatedTreatmentAtopic Dermatitis (AD)2
4Unknown StatusTreatmentVitiligo1
Not AvailableCompletedTreatmentAtopic Dermatitis (AD)1
Not AvailableCompletedTreatmentDiscoid Lupus Erythematosus (DLE)1
Not AvailableCompletedTreatmentKeratoconjunctivitis Sicca1
Not AvailableCompletedTreatmentModerate to Severe Atopic Dermatitis1
Not AvailableRecruitingNot AvailableAtopic Dermatitis (AD)1
Not AvailableWithdrawnTreatmentLupus Erythematosus, Cutaneous / Lupus Erythematosus, Discoid1

Pharmacoeconomics

Manufacturers
  • Novartis pharmaceuticals corp
Packagers
  • Novartis AG
  • Physicians Total Care Inc.
Dosage forms
FormRouteStrength
CreamTopical1 %
CreamTopical10 mg/1g
Prices
Unit descriptionCostUnit
Elidel 100 Gram Tube 1% 100 gm Tube315.76USD tube
Elidel 60 Gram Tube 1% 60 gm Tube200.05USD tube
Elidel 30 Gram Tube 1% 30 gm Tube101.44USD tube
Elidel 1% cream3.21USD g
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2200966No2006-12-192015-10-26Canada
US5912238Yes1996-12-152016-12-15Us
US6352998Yes1996-04-262016-04-26Us
US6423722Yes1998-12-262018-12-26Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP4.4Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00152 mg/mLALOGPS
logP4.36ALOGPS
logP6.81ChemAxon
logS-5.7ALOGPS
pKa (Strongest Acidic)9.96ChemAxon
pKa (Strongest Basic)-2.9ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count10ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area158.13 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity214.03 m3·mol-1ChemAxon
Polarizability87.79 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.6208
Blood Brain Barrier-0.9554
Caco-2 permeable-0.5764
P-glycoprotein substrateSubstrate0.8064
P-glycoprotein inhibitor IInhibitor0.8064
P-glycoprotein inhibitor IIInhibitor0.7014
Renal organic cation transporterNon-inhibitor0.8556
CYP450 2C9 substrateNon-substrate0.9117
CYP450 2D6 substrateNon-substrate0.8856
CYP450 3A4 substrateSubstrate0.7519
CYP450 1A2 substrateNon-inhibitor0.8678
CYP450 2C9 inhibitorNon-inhibitor0.8671
CYP450 2D6 inhibitorNon-inhibitor0.9026
CYP450 2C19 inhibitorNon-inhibitor0.8248
CYP450 3A4 inhibitorNon-inhibitor0.8672
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9326
Ames testNon AMES toxic0.6495
CarcinogenicityNon-carcinogens0.9183
BiodegradationNot ready biodegradable0.9937
Rat acute toxicity2.6919 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9787
hERG inhibition (predictor II)Non-inhibitor0.6886
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 macrolide lactams. These are cyclic polyketides containing both a cyclic amide and a cyclic ester group.
Kingdom
Organic compounds
Super Class
Phenylpropanoids and polyketides
Class
Macrolide lactams
Sub Class
Not Available
Direct Parent
Macrolide lactams
Alternative Parents
Alpha amino acid esters / Macrolides and analogues / Cyclohexyl halides / Oxanes / Piperidines / Tertiary carboxylic acid amides / Carboxylic acid esters / Cyclic ketones / Hemiacetals / Lactams
show 12 more
Substituents
Macrolide lactam / Alpha-amino acid ester / Macrolide / Alpha-amino acid or derivatives / Cyclohexyl halide / Oxane / Piperidine / Tertiary carboxylic acid amide / Carboxamide group / Carboxylic acid ester
show 27 more
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Potentiator
General Function
Tfiiic-class transcription factor binding
Specific Function
Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals. MTOR directly...
Gene Name
MTOR
Uniprot ID
P42345
Uniprot Name
Serine/threonine-protein kinase mTOR
Molecular Weight
288889.05 Da
References
  1. Reitamo S, Remitz A, Kyllonen H, Saarikko J: Topical noncorticosteroid immunomodulation in the treatment of atopic dermatitis. Am J Clin Dermatol. 2002;3(6):381-8. [PubMed:12113647]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Potentiator
General Function
Type i transforming growth factor beta receptor binding
Specific Function
Keeps in an inactive conformation TGFBR1, the TGF-beta type I serine/threonine kinase receptor, preventing TGF-beta receptor activation in absence of ligand. Recruites SMAD7 to ACVR1B which prevent...
Gene Name
FKBP1A
Uniprot ID
P62942
Uniprot Name
Peptidyl-prolyl cis-trans isomerase FKBP1A
Molecular Weight
11950.665 Da
References
  1. Reitamo S, Remitz A, Kyllonen H, Saarikko J: Topical noncorticosteroid immunomodulation in the treatment of atopic dermatitis. Am J Clin Dermatol. 2002;3(6):381-8. [PubMed:12113647]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
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. Zollinger M, Waldmeier F, Hartmann S, Zenke G, Zimmerlin AG, Glaenzel U, Baldeck JP, Schweitzer A, Berthier S, Moenius T, Grassberger MA: Pimecrolimus: absorption, distribution, metabolism, and excretion in healthy volunteers after a single oral dose and supplementary investigations in vitro. Drug Metab Dispos. 2006 May;34(5):765-74. Epub 2006 Feb 7. [PubMed:16467136]
  2. Kuper JI, D'Aprile M: Drug-Drug interactions of clinical significance in the treatment of patients with Mycobacterium avium complex disease. Clin Pharmacokinet. 2000 Sep;39(3):203-14. [PubMed:11020135]

Drug created on June 13, 2005 07:24 / Updated on September 21, 2018 00:00