Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTBUYHA)

• DTT Name: Extracellular calcium-sensing receptor (CASR)
• Synonyms: hCasR; Parathyroid cell calciumreceptor; Parathyroid cell calcium-sensing receptor 1; Parathyroid calcium receptor; Parathyroid Cell calcium-sensing receptor; PCaR1; GPRC2A; CaSR
• Gene Name: CASR
• DTT Type: Successful target; [1]
• Related Disease: Hyper-parathyroidism [ICD-11: 5A51]
• BioChemical Class: GPCR glutamate
• UniProt ID: CASR_HUMAN
• TTD ID: T92076
• Sequence:
  MAFYSCCWVLLALTWHTSAYGPDQRAQKKGDIILGGLFPIHFGVAAKDQDLKSRPESVEC
  IRYNFRGFRWLQAMIFAIEEINSSPALLPNLTLGYRIFDTCNTVSKALEATLSFVAQNKI
  DSLNLDEFCNCSEHIPSTIAVVGATGSGVSTAVANLLGLFYIPQVSYASSSRLLSNKNQF
  KSFLRTIPNDEHQATAMADIIEYFRWNWVGTIAADDDYGRPGIEKFREEAEERDICIDFS
  ELISQYSDEEEIQHVVEVIQNSTAKVIVVFSSGPDLEPLIKEIVRRNITGKIWLASEAWA
  SSSLIAMPQYFHVVGGTIGFALKAGQIPGFREFLKKVHPRKSVHNGFAKEFWEETFNCHL
  QEGAKGPLPVDTFLRGHEESGDRFSNSSTAFRPLCTGDENISSVETPYIDYTHLRISYNV
  YLAVYSIAHALQDIYTCLPGRGLFTNGSCADIKKVEAWQVLKHLRHLNFTNNMGEQVTFD
  ECGDLVGNYSIINWHLSPEDGSIVFKEVGYYNVYAKKGERLFINEEKILWSGFSREVPFS
  NCSRDCLAGTRKGIIEGEPTCCFECVECPDGEYSDETDASACNKCPDDFWSNENHTSCIA
  KEIEFLSWTEPFGIALTLFAVLGIFLTAFVLGVFIKFRNTPIVKATNRELSYLLLFSLLC
  CFSSSLFFIGEPQDWTCRLRQPAFGISFVLCISCILVKTNRVLLVFEAKIPTSFHRKWWG
  LNLQFLLVFLCTFMQIVICVIWLYTAPPSSYRNQELEDEIIFITCHEGSLMALGFLIGYT
  CLLAAICFFFAFKSRKLPENFNEAKFITFSMLIFFIVWISFIPAYASTYGKFVSAVEVIA
  ILAASFGLLACIFFNKIYIILFKPSRNTIEEVRCSTAAHAFKVAARATLRRSNVSRKRSS
  SLGGSTGSTPSSSISSKSNSEDPFPQPERQKQQQPLALTQQEQQQQPLTLPQQQRSQQQP
  RCKQKVIFGSGTVTFSLSFDEPQKNAMAHRNSTHQNSLEAQKSSDTLTRHEPLLPLQCGE
  TDLDLTVQETGLQGPVGGDQRPEVEDPEELSPALVVSSSQSFVISGGGSTVTENVVNS
• Function: Senses fluctuations in the circulating calcium concentration and modulates the production of parathyroid hormone (PTH) in parathyroid glands. The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system. The G-protein-coupled receptor activity is activated by a co-agonist mechanism: aromatic amino acids, such as Trp or Phe, act concertedly with divalent cations, such as calcium or magnesium, to achieve full receptor activation. G-protein-coupled receptor that senses changes in the extracellular concentration of calcium ions and plays a key role in maintaining calcium homeostasis.
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Class C/3 (Metabotropic glutamate/pheromone receptors) (R-HSA-420499)
  G alpha (q) signalling events (R-HSA-416476)

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Cinacalcet	DMCX0K3	Hyperparathyroidism	5A51	Approved	[1]
Etelcalcetide	DMHP9BL	Secondary hyperparathyroidism	5A51.1	Approved	[2]

4 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ASP7991	DM3TN1A	Hyperparathyroidism	5A51	Phase 2	[3]
MK-5442	DMHTIGU	Osteoporosis	FB83.0	Phase 2	[4]
ATF-936	DMWGKHZ	Osteoporosis	FB83.0	Phase 1	[5]
AXT-914	DM7ZU3B	Osteoporosis	FB83.0	Phase 1	[6]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
NPS-2143	DMQPXLF	Osteoporosis	FB83.0	Discontinued in Phase 2	[7]
R-568	DM5NWPD	N. A.	N. A.	Discontinued in Phase 2	[8]
Ronacaleret	DM10ZJP	Osteoporosis	FB83.0	Discontinued in Phase 2	[9]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
NPS-2390	DMMRY0Z	Cerebrovascular ischaemia	8B1Z	Preclinical	[10]

10 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1-arylmethylpyrrolidin-2-yl ethanol amine	DMJD1QF	Discovery agent	N.A.	Investigative	[11]
2-Furan-2-yl-3-phenethyl-3H-quinazolin-4-one	DM28XTE	Discovery agent	N.A.	Investigative	[12]
2-methyl-3-phenethyl-3H-pyrimidin-4-one	DMHYA7G	Discovery agent	N.A.	Investigative	[12]
3-Phenethyl-2-phenyl-3H-quinazolin-4-one	DMVSQFI	Discovery agent	N.A.	Investigative	[13]
AC265347	DM4G60V	Discovery agent	N.A.	Investigative	[14]
calhex 231	DMJXZD5	Discovery agent	N.A.	Investigative	[15]
calindol	DMY9P6E	Discovery agent	N.A.	Investigative	[16]
PMID15300839C17	DMWDE9A	Discovery agent	N.A.	Investigative	[17]
PMID15686947C(S)-3h	DMR7UBZ	Discovery agent	N.A.	Investigative	[18]
TAK-075	DMLOAZB	Osteoporosis	FB83.0	Investigative	[19]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Osteoporosis	FA20	Bone marrow	4.50E-02	0.23	4.1
Myelodysplastic syndrome	2C82	Bone marrow	5.81E-02	-0.03	-0.19

References

• [1] Clinical pipeline report, company report or official report of Amgen (2009).
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [3] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800035616)
• [4] Antagonist for calcium-sensing receptor. JTT-305/MK-5442. Clin Calcium. 2011 Jan;21(1):89-93.
• [5] ATF936, a novel oral calcilytic, increases bone mineral density in rats and transiently releases parathyroid hormone in humans. Bone. 2011 Aug;49(2):233-41.
• [6] AXT914 a novel, orally-active parathyroid hormone-releasing drug in two early studies of healthy volunteers and postmenopausal women. Bone. 2014 Jul;64:204-10.
• [7] Calcium-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.
• [8] Mixed-effects modeling of the pharmacodynamic response to the calcimimetic agent R-568. Clin Pharmacol Ther. 1999 Jan;65(1):40-9.
• [9] Clinical pipeline report, company report or official report of GlaxoSmithKline (2009).
• [10] The Extracellular Calcium-Sensing Receptor (CASR) Regulates Gonadotropins-Induced Meiotic Maturation of Porcine Oocytes.Biol Reprod.2015 Dec;93(6):131.
• [11] Discovery 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.
• [12] Design, new synthesis, and calcilytic activity of substituted 3H-pyrimidin-4-ones. Bioorg Med Chem Lett. 2005 May 16;15(10):2537-40.
• [13] 3H-Quinazolin-4-ones as a new calcilytic template for the potential treatment of osteoporosis. Bioorg Med Chem Lett. 2005 Mar 15;15(6):1557-60.
• [14] Characterization of highly efficacious allosteric agonists of the human calcium-sensing receptor. J Pharmacol Exp Ther. 2011 Apr;337(1):275-84.
• [15] Modeling 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.
• [16] N2-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.
• [17] N(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.
• [18] Discovery 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.
• [19] URL: 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).