Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTY6O0Q)

• DTT Name: Calcitonin gene-related peptide receptor (CGRPR)
• Synonyms: Calcitonin receptor-like receptor; Calcitonin gene-related peptide type 1 receptor; CGRPR; CGRP type 1 receptor
• Gene Name: CALCRL
• DTT Type: Successful target; [1]
• BioChemical Class: GPCR secretin
• UniProt ID: CALRL_HUMAN
• TTD ID: T32262
• Sequence:
  MEKKCTLNFLVLLPFFMILVTAELEESPEDSIQLGVTRNKIMTAQYECYQKIMQDPIQQA
  EGVYCNRTWDGWLCWNDVAAGTESMQLCPDYFQDFDPSEKVTKICDQDGNWFRHPASNRT
  WTNYTQCNVNTHEKVKTALNLFYLTIIGHGLSIASLLISLGIFFYFKSLSCQRITLHKNL
  FFSFVCNSVVTIIHLTAVANNQALVATNPVSCKVSQFIHLYLMGCNYFWMLCEGIYLHTL
  IVVAVFAEKQHLMWYYFLGWGFPLIPACIHAIARSLYYNDNCWISSDTHLLYIIHGPICA
  ALLVNLFFLLNIVRVLITKLKVTHQAESNLYMKAVRATLILVPLLGIEFVLIPWRPEGKI
  AEEVYDYIMHILMHFQGLLVSTIFCFFNGEVQAILRRNWNQYKIQFGNSFSNSEALRSAS
  YTVSTISDGPGYSHDCPSEHLNGKSIHDIENVLLKPENLYN
• Function: Receptor for calcitonin-gene-related peptide (CGRP) together with RAMP1 and receptor for adrenomedullin together with RAMP3 (By similarity). Receptor for adrenomedullin together with RAMP2. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Vascular smooth muscle contraction (hsa04270)
• Reactome Pathway:
  Calcitonin-like ligand receptors (R-HSA-419812)
  G alpha (s) signalling events (R-HSA-418555)

Molecular Interaction Atlas (MIA) of This DTT

7 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Atogepant	DMZGKXW	Migraine	8A80	Approved	[2]
Erenumab	DMWMCN0	Hyperprolactinaemia	5A60.1	Approved	[3]
Fremanezumab	DMDZY54	Hyperprolactinaemia	5A60.1	Approved	[3]
Galcanezumab	DMIZ1E8	Hyperprolactinaemia	5A60.1	Approved	[3]
Rimegepant	DMHOAUG	Migraine	8A80	Approved	[4]
Ubrogepant	DM749I3	Migraine	8A80	Approved	[5]
Zavegepant	DMTROUI	Migraine	8A80	Approved	[6]

6 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AMG 334	DMI3WFG	Migraine	8A80	Phase 2	[7]
BI-44370	DMZR9OU	Migraine	8A80	Phase 2	[8]
MK-3207	DM6OLGC	Migraine	8A80	Phase 2	[9]
Olcegepant	DMVW5KR	Migraine	8A80	Phase 2	[10]
Telcagepant	DMFT5D6	Cluster headache	8A81.0	Phase 2	[11]
LBR-101	DM4YA0D	Migraine	8A80	Phase 1	[12]

11 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BMS-694153	DM8PA3U	Migraine	8A80	Investigative	[13]
EPIMER A	DMQAEU8	Discovery agent	N.A.	Investigative	[14]
FV-Aib-TDVGPFAF	DMEI890	Discovery agent	N.A.	Investigative	[15]
FV-Hyp-TDVGPFAF	DMXQC6H	Discovery agent	N.A.	Investigative	[15]
FV-Tic-TDVGPFAF	DMBOE1U	Discovery agent	N.A.	Investigative	[15]
FVATDVGPFAF	DMDG1ZX	Discovery agent	N.A.	Investigative	[15]
FVPTDVG-Tic-FAF-Tic	DM58JFR	Discovery agent	N.A.	Investigative	[15]
FVPTDVGAFAF	DMSD7B1	Discovery agent	N.A.	Investigative	[15]
FVPTDVGPFAF	DMUVXZQ	Discovery agent	N.A.	Investigative	[15]
HCGRPalpha	DM415ZX	Discovery agent	N.A.	Investigative	[16]
ISOMER A	DMOJ52F	Discovery agent	N.A.	Investigative	[14]

References

• [1] BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia. 2014 Feb;34(2):114-25.
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019
• [6] Safety and Efficacy Trial of Zavegepant* Intranasal for Hospitalized Patients With COVID-19 Requiring Supplemental Oxygen
• [7] EHMTI-0315. AMG 334, the first potent and selective human monoclonal antibody antagonist against the CGRP receptor. J Headache Pain. 2014; 15(Suppl 1): G43.
• [8] BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine attacks: results from a phase II study. Cephalalgia. 2011 Apr;31(5):573-84.
• [9] Pharmacological properties of MK-3207, a potent and orally active calcitonin gene-related peptide receptor antagonist. J Pharmacol Exp Ther. 2010 Apr;333(1):152-60.
• [10] Olcegepant, a non-peptide CGRP1 antagonist for migraine treatment. IDrugs. 2007 Aug;10(8):566-74.
• [11] CGRP antagonists: novel concept for treatment of migraine. Med Monatsschr Pharm. 2009 May;32(5):182-5.
• [12] Safety and tolerability of LBR-101, a humanized monoclonal antibody that blocks the binding of CGRP to its receptor: Results of the Phase 1 program. Cephalalgia. 2013 Dec 23;34(7):483-492.
• [13] Discovery of (R)-4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan... J Med Chem. 2008 Aug 28;51(16):4858-61.
• [14] The identification of potent, orally bioavailable tricyclic CGRP receptor antagonists. Bioorg Med Chem Lett. 2009 Aug 15;19(16):4740-2.
• [15] Identification of the key residue of calcitonin gene related peptide (CGRP) 27-37 to obtain antagonists with picomolar affinity at the CGRP receptor. J Med Chem. 2006 Jan 26;49(2):616-24.
• [16] cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine (A-987306), a new histamine H4R antagonist that blocks pain... J Med Chem. 2008 Nov 27;51(22):7094-8.