Target Information

Target General Infomation
Target ID
T92076
Former ID
TTDS00164
Target Name
Extracellular calcium-sensing receptor
Gene Name
CASR
Synonyms
CaSR; Parathyroid Cell calcium-sensing receptor; Parathyroid calcium receptor; Parathyroid cell calciumreceptor; CASR
Target Type
Successful
Disease Cardiovascular disease; Kidney disease [ICD9: 390-459, 580-589; ICD10: I00-I99, N00-N29]
Cerebrovascular ischaemia [ICD9: 434.91; ICD10: I61-I63]
Hyperparathyroidism [ICD9: 252.02, 588.81; ICD10: E21.1]
Myelodysplastic syndrome [ICD9: 238.7; ICD10: D46]
Osteoporosis [ICD9: 733.0, V07.4; ICD10: M80-M81, Z79.890]
Secondary hyperparathyroidism [ICD10: E21.1]
Function
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.
BioChemical Class
GPCR glutamate
Target Validation
T92076
UniProt ID
P41180
Sequence
MAFYSCCWVLLALTWHTSAYGPDQRAQKKGDIILGGLFPIHFGVAAKDQDLKSRPESVEC
IRYNFRGFRWLQAMIFAIEEINSSPALLPNLTLGYRIFDTCNTVSKALEATLSFVAQNKI
DSLNLDEFCNCSEHIPSTIAVVGATGSGVSTAVANLLGLFYIPQVSYASSSRLLSNKNQF
KSFLRTIPNDEHQATAMADIIEYFRWNWVGTIAADDDYGRPGIEKFREEAEERDICIDFS
ELISQYSDEEEIQHVVEVIQNSTAKVIVVFSSGPDLEPLIKEIVRRNITGKIWLASEAWA
SSSLIAMPQYFHVVGGTIGFALKAGQIPGFREFLKKVHPRKSVHNGFAKEFWEETFNCHL
QEGAKGPLPVDTFLRGHEESGDRFSNSSTAFRPLCTGDENISSVETPYIDYTHLRISYNV
YLAVYSIAHALQDIYTCLPGRGLFTNGSCADIKKVEAWQVLKHLRHLNFTNNMGEQVTFD
ECGDLVGNYSIINWHLSPEDGSIVFKEVGYYNVYAKKGERLFINEEKILWSGFSREVPFS
NCSRDCLAGTRKGIIEGEPTCCFECVECPDGEYSDETDASACNKCPDDFWSNENHTSCIA
KEIEFLSWTEPFGIALTLFAVLGIFLTAFVLGVFIKFRNTPIVKATNRELSYLLLFSLLC
CFSSSLFFIGEPQDWTCRLRQPAFGISFVLCISCILVKTNRVLLVFEAKIPTSFHRKWWG
LNLQFLLVFLCTFMQIVICVIWLYTAPPSSYRNQELEDEIIFITCHEGSLMALGFLIGYT
CLLAAICFFFAFKSRKLPENFNEAKFITFSMLIFFIVWISFIPAYASTYGKFVSAVEVIA
ILAASFGLLACIFFNKIYIILFKPSRNTIEEVRCSTAAHAFKVAARATLRRSNVSRKRSS
SLGGSTGSTPSSSISSKSNSEDPFPQPERQKQQQPLALTQQEQQQQPLTLPQQQRSQQQP
RCKQKVIFGSGTVTFSLSFDEPQKNAMAHRNSTHQNSLEAQKSSDTLTRHEPLLPLQCGE
TDLDLTVQETGLQGPVGGDQRPEVEDPEELSPALVVSSSQSFVISGGGSTVTENVVNS
Drugs and Mode of Action
Drug(s) Cinacalcet Drug Info Approved Hyperparathyroidism [538572], [540268]
Etelcalcetide Drug Info Approved Secondary hyperparathyroidism [889446]
AMG 416 Drug Info Phase 3 Myelodysplastic syndrome [548996]
Cinacalcet Drug Info Phase 3 Cardiovascular disease; Kidney disease [538572], [540268]
ASP7991 Drug Info Phase 2 Hyperparathyroidism [524746]
KAI-4169 Drug Info Phase 2 Hyperparathyroidism [523864]
MK-5442 Drug Info Phase 2 Osteoporosis [522761]
ATF-936 Drug Info Phase 1 Osteoporosis [531447]
AXT-914 Drug Info Phase 1 Osteoporosis [532752]
NPS-2390 Drug Info Preclinical Cerebrovascular ischaemia [538860], [547300]
NPS-2143 Drug Info Discontinued in Phase 2 Osteoporosis [542168], [546895]
R-568 Drug Info Discontinued in Phase 2 Discovery agent [542190], [546233]
Ronacaleret Drug Info Discontinued in Phase 2 Osteoporosis [548261]
Antagonist 1-arylmethylpyrrolidin-2-yl ethanol amine Drug Info [527795]
2-methyl-3-phenethyl-3H-pyrimidin-4-one Drug Info [527540]
ATF-936 Drug Info [531447]
AXT-914 Drug Info [532752]
Calcium-sensing receptor antagonists Drug Info [543874]
compound (S)-3h Drug Info [527418]
compound 17 Drug Info [527165]
NPS-2143 Drug Info [532330]
Ronacaleret Drug Info [550963]
TAK-075 Drug Info [543874]
Inhibitor 2-Furan-2-yl-3-phenethyl-3H-quinazolin-4-one Drug Info [527540]
3-Phenethyl-2-phenyl-3H-quinazolin-4-one Drug Info [527460]
Modulator (allosteric modulator) AC265347 Drug Info [531336]
calhex 231 Drug Info [526833]
calindol Drug Info [527083]
Modulator AMG 416 Drug Info [532354]
Etelcalcetide Drug Info [556264]
MK-5442 Drug Info [531318]
NPS-2390 Drug Info
Agonist ASP7991 Drug Info [549352]
Cinacalcet Drug Info [550250]
KAI-4169 Drug Info [532354]
R-568 Drug Info [538155]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
Pathway Interaction Database E-cadherin signaling in keratinocytes
Reactome G alpha (q) signalling events
G alpha (i) signalling events
Class C/3 (Metabotropic glutamate/pheromone receptors)
WikiPathways GPCRs, Class C Metabotropic glutamate, pheromone
Gastrin-CREB signalling pathway via PKC and MAPK
GPCR ligand binding
GPCR downstream signaling
References
Ref 522761ClinicalTrials.gov (NCT00960934) A Dose-Ranging Study of MK-5442 in Postmenopausal Women With Osteoporosis (MK-5442-001). U.S. National Institutes of Health.
Ref 523864ClinicalTrials.gov (NCT01576146) Open-label Study to Assess the Long-term Safety and Efficacy of AMG 416 (Also Known as KAI-4169) in Patients With Secondary Hyperparathyroidism. U.S. National Institutes of Health.
Ref 524746ClinicalTrials.gov (NCT02133404) A Study to Evaluate the Effect of ASP7991 in Secondary Hyperparathyroidism Patients Undergoing Hemodialysis. U.S. National Institutes of Health.
Ref 531447ATF936, a novel oral calcilytic, increases bone mineral density in rats and transiently releases parathyroid hormone in humans. Bone. 2011 Aug;49(2):233-41.
Ref 532752AXT914 a novel, orally-active parathyroid hormone-releasing drug in two early studies of healthy volunteers and postmenopausal women. Bone. 2014 Jul;64:204-10.
Ref 538572FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 021688.
Ref 538860(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 1384).
Ref 540268(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 3308).
Ref 542168(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 716).
Ref 542190(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 718).
Ref 546233Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007039)
Ref 546895Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010915)
Ref 547300Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014988)
Ref 548261Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800023902)
Ref 548996Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800031284)
Ref 889446Drugs@FDA (Edaravone)
Ref 526833Modeling and mutagenesis of the binding site of Calhex 231, a novel negative allosteric modulator of the extracellular Ca(2+)-sensing receptor. J Biol Chem. 2003 Dec 5;278(49):49487-94. Epub 2003 Sep 23.
Ref 527083N2-benzyl-N1-(1-(1-naphthyl)ethyl)-3-phenylpropane-1,2-diamines and conformationally restrained indole analogues: development of calindol as a new calcimimetic acting at the calcium sensing receptor.Bioorg Med Chem Lett. 2004 Jun 21;14(12):3345-9.
Ref 527165N(1)-Arylsulfonyl-N(2)-(1-(1-naphthyl)ethyl)-1,2-diaminocyclohexanes: a new class of calcilytic agents acting at the calcium-sensing receptor. Chembiochem. 2004 Aug 6;5(8):1131-6.
Ref 527418Discovery and structure-activity relationships of 2-benzylpyrrolidine-substituted aryloxypropanols as calcium-sensing receptor antagonists. Bioorg Med Chem Lett. 2005 Feb 15;15(4):1225-8.
Ref 527460Bioorg Med Chem Lett. 2005 Mar 15;15(6):1557-60.3H-Quinazolin-4-ones as a new calcilytic template for the potential treatment of osteoporosis.
Ref 527540Bioorg Med Chem Lett. 2005 May 16;15(10):2537-40.Design, new synthesis, and calcilytic activity of substituted 3H-pyrimidin-4-ones.
Ref 527795Discovery of novel 1-arylmethyl pyrrolidin-2-yl ethanol amines as calcium-sensing receptor antagonists. Bioorg Med Chem Lett. 2005 Dec 15;15(24):5478-82. Epub 2005 Oct 10.
Ref 531318Antagonist for calcium-sensing receptor. JTT-305/MK-5442. Clin Calcium. 2011 Jan;21(1):89-93.
Ref 531336Characterization of highly efficacious allosteric agonists of the human calcium-sensing receptor. J Pharmacol Exp Ther. 2011 Apr;337(1):275-84.
Ref 531447ATF936, a novel oral calcilytic, increases bone mineral density in rats and transiently releases parathyroid hormone in humans. Bone. 2011 Aug;49(2):233-41.
Ref 532330Calcium-sensing receptor antagonist (calcilytic) NPS 2143 specifically blocks the increased secretion of endogenous Abeta42 prompted by exogenous fibrillary or soluble Abeta25-35 in human cortical astrocytes and neurons-therapeutic relevance to Alzheimer's disease. Biochim Biophys Acta. 2013 Oct;1832(10):1634-52.
Ref 532354Pharmacology of AMG 416 (Velcalcetide), a novel peptide agonist of the calcium-sensing receptor, for the treatment of secondary hyperparathyroidism in hemodialysis patients. J Pharmacol Exp Ther. 2013 Aug;346(2):229-40.
Ref 532752AXT914 a novel, orally-active parathyroid hormone-releasing drug in two early studies of healthy volunteers and postmenopausal women. Bone. 2014 Jul;64:204-10.
Ref 538155Mixed-effects modeling of the pharmacodynamic response to the calcimimetic agent R-568. Clin Pharmacol Ther. 1999 Jan;65(1):40-9.
Ref 543874(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 54).
Ref 549352Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800035616)
Ref 550250Clinical pipeline report, company report or official report of Amgen (2009).
Ref 550963Clinical pipeline report, company report or official report of GlaxoSmithKline (2009).
Ref 556264Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.

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