Olcegepant

Identification

Name
Olcegepant
Accession Number
DB04869
Type
Small Molecule
Groups
Investigational
Description

Boehringer Ingelheim Pharmaceuticals’ olcegepant (BIBN 4096) is a selective Calcitonin Gene-Related Peptide (CGRP) antagonist, a new class of drugs in development for the treatment of acute migraine attacks. Olcegepant is undergoing phase II trials in Europe and the US, with preliminary results suggesting that CGRP antagonists may represent a potential new approach to the treatment of migraine.

Structure
Thumb
Synonyms
Not Available
External IDs
BIBN 4096 / BIBN 4096 BS / BIBN-4096 BS / BIBN-4096BS
Categories
UNII
WOA5J8TX6M
CAS number
204697-65-4
Weight
Average: 869.645
Monoisotopic: 867.206690953
Chemical Formula
C38H47Br2N9O5
InChI Key
ITIXDWVDFFXNEG-JHOUSYSJSA-N
InChI
InChI=1S/C38H47Br2N9O5/c39-29-21-25(22-30(40)34(29)50)23-33(45-37(53)48-15-10-28(11-16-48)49-24-26-5-1-2-6-31(26)44-38(49)54)35(51)43-32(7-3-4-12-41)36(52)47-19-17-46(18-20-47)27-8-13-42-14-9-27/h1-2,5-6,8-9,13-14,21-22,28,32-33,50H,3-4,7,10-12,15-20,23-24,41H2,(H,43,51)(H,44,54)(H,45,53)/t32-,33+/m0/s1
IUPAC Name
(2R)-N-[(2S)-6-amino-1-oxo-1-[4-(pyridin-4-yl)piperazin-1-yl]hexan-2-yl]-3-(3,5-dibromo-4-hydroxyphenyl)-2-({hydroxy[4-(2-hydroxy-3,4-dihydroquinazolin-3-yl)piperidin-1-yl]methylidene}amino)propanimidic acid
SMILES
[H][C@@](CCCCN)(N=C(O)[C@@]([H])(CC1=CC(Br)=C(O)C(Br)=C1)N=C(O)N1CCC(CC1)N1CC2=CC=CC=C2N=C1O)C(=O)N1CCN(CC1)C1=CC=NC=C1

Pharmacology

Indication

For the treatment of migraine headaches.

Pharmacodynamics

Olcegepant is a calcitonin gene-related peptide (CGRP) antagonist. In preclinical studies, olcegepant attenuated arterial dilation induced by CGRP or electrical stimulation. In a phase II clinical trial, olcegepant reduced the severity of headache in 60% of migraine sufferers and met secondary endpoints including headache-free rate and rate of sustained response. Only mild-to-moderate transient adverse events were observed, with no adverse cardiovascular symptoms reported. The compound appears to be an effective anti-migraine medication that is well tolerated and does not display the vasoconstrictive effect that precludes the use of triptans and dihydroergotamine in certain patients.

Mechanism of action

Migraine involves dysfunction of brainstem pathways that normally modulate sensory input. The involvement of calcitonin gene-related peptide (CGRP) in migraine pathology is supported by both clinical and experimental evidence. The release of CGRP and other neuropeptides from trigeminal nerves is thought to mediate neurogeate inflammation within the meninges which contributes to the generation of severe cerebral pain experienced during migraine attack. CGRP antagonists such as olcegepant bind at CGRP receptors, blocking the effect CGRP and thus reducing inflammation.

TargetActionsOrganism
UCalcitonin gene-related peptide 1Not AvailableHuman
UCalcitonin gene-related peptide type 1 receptorNot AvailableHuman
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Recober A, Russo AF: Olcegepant, a non-peptide CGRP1 antagonist for migraine treatment. IDrugs. 2007 Aug;10(8):566-74. [PubMed:17665333]
External Links
PubChem Compound
6918509
PubChem Substance
175426877
ChemSpider
5293706
BindingDB
50184069
ChEMBL
CHEMBL207197
HET
3N6
Wikipedia
Olcegepant
PDB Entries
3n7r / 3n7s

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentMigraine Disorders1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0316 mg/mLALOGPS
logP3.55ALOGPS
logP1.08ChemAxon
logS-4.4ALOGPS
pKa (Strongest Acidic)4.17ChemAxon
pKa (Strongest Basic)10.24ChemAxon
Physiological Charge3ChemAxon
Hydrogen Acceptor Count13ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area186.94 Å2ChemAxon
Rotatable Bond Count12ChemAxon
Refractivity216.88 m3·mol-1ChemAxon
Polarizability84.67 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9692
Blood Brain Barrier-0.8022
Caco-2 permeable-0.779
P-glycoprotein substrateSubstrate0.8342
P-glycoprotein inhibitor INon-inhibitor0.696
P-glycoprotein inhibitor IINon-inhibitor0.8823
Renal organic cation transporterNon-inhibitor0.8041
CYP450 2C9 substrateNon-substrate0.8591
CYP450 2D6 substrateNon-substrate0.7829
CYP450 3A4 substrateNon-substrate0.5
CYP450 1A2 substrateNon-inhibitor0.8027
CYP450 2C9 inhibitorNon-inhibitor0.6565
CYP450 2D6 inhibitorNon-inhibitor0.808
CYP450 2C19 inhibitorNon-inhibitor0.6908
CYP450 3A4 inhibitorNon-inhibitor0.6928
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7051
Ames testNon AMES toxic0.6406
CarcinogenicityNon-carcinogens0.8528
BiodegradationNot ready biodegradable0.9946
Rat acute toxicity2.2550 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7242
hERG inhibition (predictor II)Inhibitor0.8525
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 dipeptides. These are organic compounds containing a sequence of exactly two alpha-amino acids joined by a peptide bond.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Dipeptides
Alternative Parents
Tyrosine and derivatives / Phenylalanine and derivatives / N-acyl-alpha amino acids and derivatives / N-carbamoyl-alpha amino acids and derivatives / Alpha amino acid amides / N-arylpiperazines / Pyridinylpiperazines / Quinazolines / Amphetamines and derivatives / Piperidinecarboxamides
show 18 more
Substituents
Alpha-dipeptide / Tyrosine or derivatives / Phenylalanine or derivatives / N-acyl-alpha amino acid or derivatives / N-carbamoyl-alpha-amino acid or derivatives / Alpha-amino acid amide / Pyridinylpiperazine / N-arylpiperazine / Diazanaphthalene / N-substituted-alpha-amino acid
show 49 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Receptor binding
Specific Function
CGRP induces vasodilation. It dilates a variety of vessels including the coronary, cerebral and systemic vasculature. Its abundance in the CNS also points toward a neurotransmitter or neuromodulato...
Gene Name
CALCA
Uniprot ID
P06881
Uniprot Name
Calcitonin gene-related peptide 1
Molecular Weight
13897.755 Da
References
  1. Recober A, Russo AF: Olcegepant, a non-peptide CGRP1 antagonist for migraine treatment. IDrugs. 2007 Aug;10(8):566-74. [PubMed:17665333]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General 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.
Specific Function
Adrenomedullin receptor activity
Gene Name
CALCRL
Uniprot ID
Q16602
Uniprot Name
Calcitonin gene-related peptide type 1 receptor
Molecular Weight
52928.98 Da
References
  1. Walker CS, Raddant AC, Woolley MJ, Russo AF, Hay DL: CGRP receptor antagonist activity of olcegepant depends on the signalling pathway measured. Cephalalgia. 2017 Jan 1:333102417691762. doi: 10.1177/0333102417691762. [PubMed:28165287]

Drug created on October 20, 2007 04:10 / Updated on November 02, 2018 06:06