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Identification
Name Cinacalcet
Accession Number DB01012 (APRD00872)
Type small molecule
Groups approved
Description

Cinacalcet (INN) is a drug that acts as a calcimimetic (i.e. it mimics the action of calcium on tissues) by allosteric activation of the calcium-sensing receptor that is expressed in various human organ tissues. It is sold by Amgen under the trade name Sensipar® in North America and Australia and as Mimpara® in Europe. Cinacalcet is used to treat hyperparathyroidism (elevated parathyroid hormone levels), a consequence of parathyroid tumors and chronic renal failure.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms Not Available
Brand names
  • Sensipar
Brand name mixtures Not Available
Categories
  • Calcimimetics
CAS number 226256-56-0
Weight Average: 357.412
Monoisotopic: 357.170434324
Chemical Formula C22H22F3N
InChI Key InChIKey=VDHAWDNDOKGFTD-MRXNPFEDSA-N
InChI
InChI=1S/C22H22F3N/c1-16(20-13-5-10-18-9-2-3-12-21(18)20)26-14-6-8-17-7-4-11-19(15-17)22(23,24)25/h2-5,7,9-13,15-16,26H,6,8,14H2,1H3/t16-/m1/s1
Plain Text
IUPAC Name
[(1R)-1-(naphthalen-1-yl)ethyl]({3-[3-(trifluoromethyl)phenyl]propyl})amine
SMILES
C[C@@H](NCCCC1=CC(=CC=C1)C(F)(F)F)C1=CC=CC2=C1C=CC=C2
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Naphthalenes
  • Phenylpropylamines
Substructures
  • Naphthalenes
  • Aliphatic and Aryl Amines
  • Halogen Derivatives
  • Benzene and Derivatives
  • Aromatic compounds
  • Phenylpropylamines
Pharmacology
Indication For the treatment of secondary hyperparathyroidism in patients with Chronic Kidney Disease who are on hemodialysis or peritoneal dialysis. Also for the treatment of hypercalcemia in patients with parathyroid carcinoma.
Pharmacodynamics Cinacalcet is a drug that acts as a calcimimetic (i.e. it mimics the action of calcium on tissues). Secondary hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) is a progressive disease, associated with increases in parathyroid hormone (PTH) levels and derangements in calcium and phosphorus metabolism. Increased PTH stimulates osteoclastic activity resulting in cortical bone resorption and marrow fibrosis. The goals of treatment of secondary hyperparathyroidism are to lower levels of PTH, calcium, and phosphorus in the blood, in order to prevent progressive bone disease and the systemic consequences of disordered mineral metabolism. In CKD patients on dialysis with uncontrolled secondary HPT, reductions in PTH are associated with a favorable impact on bone-specific alkaline phosphatase (BALP), bone turnover and bone fibrosis. Cinacalcet reduces calcium levels by increasing the sensitivity of the calcium sensing receptor to extracellular calcium.
Mechanism of action The calcium-sensing receptors on the surface of the chief cell of the parathyroid gland is the principal regulator of parathyroid hormone secretion (PTH). Cinacalcet directly lowers parathyroid hormone levels by increasing the sensitivity of the calcium sensing receptors to activation by extracellular calcium, resulting in the inhibition of PTH secretion. The reduction in PTH is associated with a concomitant decrease in serum calcium levels.
Absorption Rapidly absorbed following oral administration.
Volume of distribution
  • 1000 L
Protein binding Approximately 93 to 97% bound to plasma proteins.
Metabolism

Metabolism is hepatic by multiple enzymes, primarily CYP3A4, CYP2D6, and CYP1A2. After administration of a 75 mg radiolabeled dose to healthy volunteers, cinacalcet was rapidly and extensively metabolized via: 1) oxidative N-dealkylation to hydrocinnamic acid and hydroxy-hydrocinnamic acid, which are further metabolized via ß-oxidation and glycine conjugation; the oxidative N-dealkylation process also generates metabolites that contain the naphthalene ring; and 2) oxidation of the naphthalene ring on the parent drug to form dihydrodiols, which are further conjugated with glucuronic acid.
Route of elimination Cinacalcet is metabolized by multiple enzymes, primarily CYP3A4, CYP2D6 and CYP1A2. Renal excretion of metabolites was the primary route of elimination of radioactivity.
Half life Terminal half-life is 30 to 40 hours. The mean half-life of cinacalcet is prolonged by 33% and 70% in patients with moderate and severe hepatic impairment, respectively.
Clearance Not Available
Toxicity Doses titrated up to 300 mg once daily have been safely administered to patients on dialysis. Overdosage of cinacalcet may lead to hypocalcemia.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Amgen inc
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Sensipar 90 mg tablet 44.03 USD tablet
Sensipar 60 mg tablet 29.35 USD tablet
Sensipar 30 mg tablet 14.69 USD tablet
Patents
Country Patent Number Approved Expires
United States 6011068 1996-12-14 2016-12-14
United States 6211244 1995-10-23 2015-10-23
Canada 2202879 2005-08-30 2015-10-23
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
water solubility Slightly soluble (in HCl salt form) PhysProp
logP 6.5 PhysProp
Predicted Properties
Property Value Source
water solubility 5.59e-05 g/l ALOGPS
logP 5.57 ALOGPS
logP 6.27 ChemAxon Molconvert
logS -6.81 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 1 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 12.03 ChemAxon Molconvert
rotatable bond count 7 ChemAxon Molconvert
refractivity 100.12 ChemAxon Molconvert
polarizability 37.90 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Torres PU: Cinacalcet HCl: a novel treatment for secondary hyperparathyroidism caused by chronic kidney disease. J Ren Nutr. 2006 Jul;16(3):253-8. Pubmed
  2. Padhi D, Harris R: Clinical pharmacokinetic and pharmacodynamic profile of cinacalcet hydrochloride. Clin Pharmacokinet. 2009;48(5):303-11. doi: 10.2165/00003088-200948050-00002. Pubmed
  3. Dong BJ: Cinacalcet: An oral calcimimetic agent for the management of hyperparathyroidism. Clin Ther. 2005 Nov;27(11):1725-51. Pubmed
External Links
Resource Link
PubChem Compound 156419 Link_out
PubChem Substance 46506315 Link_out
ChemSpider 137743 Link_out
ChEBI 48390 Link_out
ChEMBL 48390 Link_out
Therapeutic Targets Database DAP000256 Link_out
PharmGKB PA10044 Link_out
Drug Product Database 2257157 Link_out
RxList http://www.rxlist.com/cgi/generic3/sensipar.htm Link_out
Drugs.com http://www.drugs.com/cdi/cinacalcet.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Cinacalcet Link_out
ATC Codes
  • H05BX01
AHFS Codes
  • 92:00.00
PDB Entries Not Available
FDA label show (278.3 KB)
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions
  • Food markedly increases product bioavailability.
  • Peak levels and area under curve (drug exposure) are increased (82% and 68% respectively) when product is taken with a lipid-rich meal.
  • Take with food or soon after a meal.
Targets

1. Extracellular calcium-sensing receptor

Pharmacological action: yes
Actions: agonist

Senses changes in the extracellular concentration of calcium ions. The activity of this receptor is mediated by a G- protein that activates a phosphatidylinositol-calcium second messenger system

Organism class: human
UniProt ID: P41180 Link_out
Gene: CASR Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. de Francisco AL: Cinacalcet HCl: a novel therapeutic for hyperparathyroidism. Expert Opin Pharmacother. 2005 Mar;6(3):441-52. Pubmed
  2. Rothe HM, Shapiro WB, Sun WY, Chou SY: Calcium-sensing receptor gene polymorphism Arg990Gly and its possible effect on response to cinacalcet HCl. Pharmacogenet Genomics. 2005 Jan;15(1):29-34. Pubmed
  3. Tasic V: Management of renal osteodystrophy in children. Turk J Pediatr. 2005;47 Suppl:13-8. Pubmed
  4. Moe SM, Cunningham J, Bommer J, Adler S, Rosansky SJ, Urena-Torres P, Albizem MB, Guo MD, Zani VJ, Goodman WG, Sprague SM: Long-term treatment of secondary hyperparathyroidism with the calcimimetic cinacalcet HCl. Nephrol Dial Transplant. 2005 Oct;20(10):2186-93. Epub 2005 Jul 19. Pubmed
  5. Cunningham J: Management of secondary hyperparathyroidism. Ther Apher Dial. 2005 Aug;9 Suppl 1:S35-40. Pubmed
  6. Eriguchi R, Umakoshi J, Tominaga Y, Sato Y: Successful treatment of inoperable recurrent secondary hyperparathyroidism with cinacalcet HCl. NDT Plus. 2008 Aug;1(4):218-220. Epub 2008 May 25. Pubmed
  7. Belozeroff V, Goodman WG, Ren L, Kalantar-Zadeh K: Cinacalcet lowers serum alkaline phosphatase in maintenance hemodialysis patients. Clin J Am Soc Nephrol. 2009 Mar;4(3):673-9. Epub 2009 Mar 4. Pubmed
  8. Meola M, Petrucci I, Barsotti G: Long-term treatment with cinacalcet and conventional therapy reduces parathyroid hyperplasia in severe secondary hyperparathyroidism. Nephrol Dial Transplant. 2009 Mar;24(3):982-9. Epub 2009 Jan 30. Pubmed
  9. Drueke TB, Ritz E: Treatment of secondary hyperparathyroidism in CKD patients with cinacalcet and/or vitamin D derivatives. Clin J Am Soc Nephrol. 2009 Jan;4(1):234-41. Epub 2008 Dec 3. Pubmed
  10. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
Enzymes

1. Cytochrome P450 3A4

Actions: substrate

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 xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Padhi D, Harris R: Clinical pharmacokinetic and pharmacodynamic profile of cinacalcet hydrochloride. Clin Pharmacokinet. 2009;48(5):303-11. Pubmed
  2. Dong BJ: Cinacalcet: An oral calcimimetic agent for the management of hyperparathyroidism. Clin Ther. 2005 Nov;27(11):1725-51. Pubmed

2. Cytochrome P450 2D6

Actions: inhibitor

Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Padhi D, Harris R: Clinical pharmacokinetic and pharmacodynamic profile of cinacalcet hydrochloride. Clin Pharmacokinet. 2009;48(5):303-11. Pubmed
  2. Dong BJ: Cinacalcet: An oral calcimimetic agent for the management of hyperparathyroidism. Clin Ther. 2005 Nov;27(11):1725-51. Pubmed
  3. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

3. Cytochrome P450 1A2

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Padhi D, Harris R: Clinical pharmacokinetic and pharmacodynamic profile of cinacalcet hydrochloride. Clin Pharmacokinet. 2009;48(5):303-11. Pubmed
  2. Dong BJ: Cinacalcet: An oral calcimimetic agent for the management of hyperparathyroidism. Clin Ther. 2005 Nov;27(11):1725-51. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on April 19, 2011 15:07

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.