Identification

Name
Macimorelin
Accession Number
DB13074  (DB06066, DB05917)
Type
Small Molecule
Groups
Approved, Investigational
Description

Macimorelin, a novel and orally active ghrelin mimetic that stimulates GH secretion, is used in the diagnosis of adult GH deficiency (AGHD). More specifically, macimorelin is a peptidomimetic growth hormone secretagogue (GHS) that acts as an agonist of GH secretagogue receptor, or ghrelin receptor (GHS-R1a) to dose-dependently increase GH levels [3]. Growth hormone secretagogues (GHS) represent a new class of pharmacological agents which have the potential to be used in numerous clinical applications. They include treatment for growth retardation in children and cachexia associated with chronic disease such as AIDS and cancer.

Growth hormone (GH) is classically linked with linear growth during childhood. In deficiency of this hormone, AGHD is commonly associated with increased fat mass (particularly in the abdominal region), decreased lean body mass, osteopenia, dyslipidemia, insulin resistance, and/or glucose intolerance overtime. In addition, individuals with may be susceptible to cardiovascular complications from altered structures and function [5]. Risk factors of AGHD include a history of childhood-onset GH deficiency or with hypothalamic/pituitary disease, surgery, or irradiation to these areas, head trauma, or evidence of other pituitary hormone deficiencies [3]. While there are various therapies available such as GH replacement therapy, the absence of panhypopituitarism and low serum IGF-I levels with nonspecific clinical symptoms pose challenges to the detection and diagnosis of AGHD. The diagnosis of AGHD requires biochemical confirmation with at least 1 GH stimulation test [3]. Macimorelin is clinically useful since it displays good stability and oral bioavailability with comparable affinity to ghrelin receptor as its endogenous ligand. In clinical studies involving healthy subjects, macimorelin stimulated GH release in a dose-dependent manner with good tolerability [3].

Macimorelin, developed by Aeterna Zentaris, was approved by the FDA in December 2017 under the market name Macrilen for oral solution.

Structure
Thumb
Synonyms
Not Available
External IDs
ARD 07 / ARD-07 / D-87575 / EP 1572 / EP-01572 / EP-1572 / JMV-1843
Product Ingredients
IngredientUNIICASInChI Key
Macimorelin acetateAQZ1003RMG945212-59-9WVDSKQXKCDZXLH-OHIDFYLOSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
MacrilenGranule, for solution60 mg/1mgOralStrongbridge U.S. Inc2018-01-29Not applicableUs
Categories
UNII
8680B21W73
CAS number
381231-18-1
Weight
Average: 474.565
Monoisotopic: 474.23793885
Chemical Formula
C26H30N6O3
InChI Key
UJVDJAPJQWZRFR-DHIUTWEWSA-N
InChI
InChI=1S/C26H30N6O3/c1-26(2,27)25(35)31-22(11-16-13-28-20-9-5-3-7-18(16)20)24(34)32-23(30-15-33)12-17-14-29-21-10-6-4-8-19(17)21/h3-10,13-15,22-23,28-29H,11-12,27H2,1-2H3,(H,30,33)(H,31,35)(H,32,34)/t22-,23-/m1/s1
IUPAC Name
(2R)-2-(2-amino-2-methylpropanamido)-3-(1H-indol-3-yl)-N-[(1R)-2-(1H-indol-3-yl)-1-formamidoethyl]propanamide
SMILES
CC(C)(N)C(=O)N[C@H](CC1=CNC2=CC=CC=C12)C(=O)N[C@H](CC1=CNC2=CC=CC=C12)NC=O

Pharmacology

Indication

Indicated for the diagnosis of adult growth hormone deficiency (AGHD) [Label].

Associated Conditions
Pharmacodynamics

Maximum GH levels from stimulation are observed between 30 to 90 minutes after administration of macimorelin [Label]. Increase in the QTcF interval may be observed from macimorelin administration [Label].

Mechanism of action

Ghrelin is an endogenous ligand for the GH secretagogue receptor that is also called the ghrelin receptor (GHS-R1a). Upon activation of the receptor, ghrelin serves to increase growth hormone (GH) secretion. Macimorelin mimics the actions of ghrelin by stimulating GH release. As a synthetic agonist, it activates growth hormone secretagogue receptors present in the pituitary and hypothalamus.

TargetActionsOrganism
UGrowth hormone secretagogue receptor type 1
agonist
Human
Absorption

Macimorelin is a novel, synthetic ghrelin agonist, which is readily absorbed from the gastrointestinal tract [4]. The maximum plasma concentration (Cmax) was observed between 0.5 and 1.5 hours following oral administration of 0.5mg/kg macimorelin to patients with AGHD under fasting for at least 8 hours. Higher doses of drug demonstrate a dose-proportional increase in plasma concentrations [4]. A liquid meal decreased the macimorelin Cmax and AUC by 55% and 49%, respectively [Label].

Volume of distribution

Following a single oral dose of 0.5 mg/kg macimorelin, the mean volume of distribution of the central compartment is 5,733.4 ± 565.7L [4].

Protein binding
Not Available
Metabolism

Macimorelin predominantly undergoes CYP3A4-mediated metabolism according to an in vitro human liver microsomes study [Label].

Route of elimination
Not Available
Half life

The mean terminal half-life (T1/2) is 4.1 hours following administration of a single oral dose of 0.5 mg macimorelin/kg body weight in healthy subjects [Label].

Clearance

Following a single oral dose of 0.5 mg/kg macimorelin, the mean clearance over the fraction absorbed (Cl/F) was 37,411.0 ± 4,554.6 mL/min [4].

Toxicity

Macimorelin has not shown to demonstrate mutagenic properties according to bacterial assays. It also did not induce any mutations or clastogenic effects in mouse lymphoma cells with or without metabolic activation. Studies assessing the carcinogenic potential or effect on fertility of macimorelin have not been conducted [Label].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Macimorelin can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Macimorelin.
3,5-diiodothyropropionic acidThe metabolism of Macimorelin can be decreased when combined with 3,5-diiodothyropropionic acid.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Macimorelin.
5-androstenedioneThe metabolism of Macimorelin can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Macimorelin can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of Macimorelin can be decreased when combined with 6-O-benzylguanine.
AbemaciclibThe metabolism of Macimorelin can be decreased when combined with Abemaciclib.
AbexinostatThe risk or severity of QTc prolongation can be increased when Abexinostat is combined with Macimorelin.
AbirateroneThe metabolism of Macimorelin can be decreased when combined with Abiraterone.
Food Interactions
Not Available

References

General References
  1. Guerlavais V, Boeglin D, Mousseaux D, Oiry C, Heitz A, Deghenghi R, Locatelli V, Torsello A, Ghe C, Catapano F, Muccioli G, Galleyrand JC, Fehrentz JA, Martinez J: New active series of growth hormone secretagogues. J Med Chem. 2003 Mar 27;46(7):1191-203. [PubMed:12646029]
  2. Broglio F, Boutignon F, Benso A, Gottero C, Prodam F, Arvat E, Ghe C, Catapano F, Torsello A, Locatelli V, Muccioli G, Boeglin D, Guerlavais V, Fehrentz JA, Martinez J, Ghigo E, Deghenghi R: EP1572: a novel peptido-mimetic GH secretagogue with potent and selective GH-releasing activity in man. J Endocrinol Invest. 2002 Sep;25(8):RC26-8. [PubMed:12240910]
  3. Garcia JM, Swerdloff R, Wang C, Kyle M, Kipnes M, Biller BM, Cook D, Yuen KC, Bonert V, Dobs A, Molitch ME, Merriam GR: Macimorelin (AEZS-130)-stimulated growth hormone (GH) test: validation of a novel oral stimulation test for the diagnosis of adult GH deficiency. J Clin Endocrinol Metab. 2013 Jun;98(6):2422-9. doi: 10.1210/jc.2013-1157. Epub 2013 Apr 4. [PubMed:23559086]
  4. Piccoli F, Degen L, MacLean C, Peter S, Baselgia L, Larsen F, Beglinger C, Drewe J: Pharmacokinetics and pharmacodynamic effects of an oral ghrelin agonist in healthy subjects. J Clin Endocrinol Metab. 2007 May;92(5):1814-20. doi: 10.1210/jc.2006-2160. Epub 2007 Feb 6. [PubMed:17284637]
  5. Fukuda I, Hizuka N, Muraoka T, Ichihara A: Adult growth hormone deficiency: current concepts. Neurol Med Chir (Tokyo). 2014;54(8):599-605. Epub 2014 Jul 28. [PubMed:25070016]
External Links
KEGG Drug
D10563
ChemSpider
7980698
BindingDB
50125886
ChEMBL
CHEMBL278623
Wikipedia
Macimorelin
ATC Codes
V04CD06 — Macimorelin
FDA label
Download (280 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2RecruitingTreatmentCancer Cachexia1
3CompletedDiagnosticGrowth Hormone Deficiency With Pituitary Anomalies1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Granule, for solutionOral60 mg/1mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8192719No2007-10-122027-10-12Us
US6861409No2002-08-012022-08-01Us

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00616 mg/mLALOGPS
logP1.77ALOGPS
logP1.67ChemAxon
logS-4.9ALOGPS
pKa (Strongest Acidic)12.4ChemAxon
pKa (Strongest Basic)8.34ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count6ChemAxon
Polar Surface Area144.9 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity133.14 m3·mol-1ChemAxon
Polarizability49.05 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

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
N-acyl-alpha amino acids and derivatives / Tryptamines and derivatives / Alpha amino acid amides / 3-alkylindoles / Substituted pyrroles / Fatty amides / Benzenoids / Heteroaromatic compounds / Secondary carboxylic acid amides / Azacyclic compounds
show 4 more
Substituents
Alpha-dipeptide / N-acyl-alpha amino acid or derivatives / Alpha-amino acid amide / Triptan / N-substituted-alpha-amino acid / Alpha-amino acid or derivatives / 3-alkylindole / Indole or derivatives / Indole / Fatty acyl
show 21 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Agonist
General Function
Peptide hormone binding
Specific Function
Receptor for ghrelin, coupled to G-alpha-11 proteins. Stimulates growth hormone secretion. Binds also other growth hormone releasing peptides (GHRP) (e.g. Met-enkephalin and GHRP-6) as well as non-...
Gene Name
GHSR
Uniprot ID
Q92847
Uniprot Name
Growth hormone secretagogue receptor type 1
Molecular Weight
41328.045 Da

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da

Drug created on October 20, 2016 20:42 / Updated on November 02, 2018 09:10