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Details

Stereochemistry ABSOLUTE
Molecular Formula C21H19FN6O2
Molecular Weight 406.413
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of LORLATINIB

SMILES

C[C@H]1OC2=CC(=CN=C2N)C3=C(C#N)N(C)N=C3CN(C)C(=O)C4=C1C=C(F)C=C4

InChI

InChIKey=IIXWYSCJSQVBQM-LLVKDONJSA-N
InChI=1S/C21H19FN6O2/c1-11-15-7-13(22)4-5-14(15)21(29)27(2)10-16-19(17(8-23)28(3)26-16)12-6-18(30-11)20(24)25-9-12/h4-7,9,11H,10H2,1-3H3,(H2,24,25)/t11-/m1/s1

HIDE SMILES / InChI

Molecular Formula C21H19FN6O2
Molecular Weight 406.413
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry
Defined Stereocenters 1 / 1
E/Z Centers 0
Optical Activity UNSPECIFIED

Description

Lorlatinib is an investigational medicine that inhibits the anaplastic lymphoma kinase (ALK) and ROS1 proto-oncogene. Lorlatinib was specifically designed to inhibit tumor mutations that drive resistance to other ALK inhibitors. Lorlatinib has in vitro activity against ALK and number of other tyrosine kinase receptor related targets including ROS1, TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK. Lorlatinib demonstrated in vitro activity against multiple mutant forms of the ALK enzyme, including some mutations detected in tumors at the time of disease progression on crizotinib and other ALK inhibitors. Moreover, lorlatinib possesses the capability to cross the blood-brain barrier, allowing it to reach and treat progressive or worsening brain metastases as well. Lorlatinib is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) indicated for the treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on a) the prior use of crizotinib and at least one other ALK inhibitor for metastatic disease, or b) the prior use of alectinib as the first ALK inhibitor therapy for metastatic disease, or c) the prior use of certinib as the first ALK inhibitor therapy for metastatic disease.

CNS Activity

Originator

Approval Year

PubMed

PubMed

TitleDatePubMed
Patents

Sample Use Guides

In Vivo Use Guide
The recommended dosage is 100 mg orally once daily.
Route of Administration: Oral
In Vitro Use Guide
Mutant ALKG1128A, ALKF1174L, ALKR1192P, ALKF1245C and ALKR1275Q responded to PF-06463922 with IC50 values similar to that of wild-type, two mutants – ALKI1171N and ALKY1278S – were more resistant, with 4- and 2.8-fold (3.21 nM and 2.27 nM) respectively of the IC50 of wild-type ALK kinase.
Substance Class Chemical
Created
by admin
on Mon Oct 21 22:49:43 UTC 2019
Edited
by admin
on Mon Oct 21 22:49:43 UTC 2019
Record UNII
OSP71S83EU
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
LORLATINIB
INN   USAN   WHO-DD  
INN   USAN  
Official Name English
LORBRENA
Brand Name English
LORLATINIB [WHO-DD]
Common Name English
PF-06463922
Code English
LORLATINIB [INN]
Common Name English
(10R)-7-AMINO-12-FLUORO-2,10,16-TRIMETHYL-15-OXO-10,15,16,17-TETRAHYDRO-2H-4,8- METHENOPYRAZOLO(4,3-H)(2,5,11)BENZOXADIAZACYCLOTETRADECINE-3-CARBONITRILE
Systematic Name English
LORLATINIB [USAN]
Common Name English
2H-4,8-METHENOPYRAZOLO(4,3-H)(2,5,11)BENZOXADIAZACYCLOTETRADECINE-3-CARBONITRILE, 7-AMINO-12-FLUORO-10,15,16,17-TETRAHYDRO-2,10,16-TRIMETHYL-15-OXO-, (10R)-
Systematic Name English
Classification Tree Code System Code
NCI_THESAURUS C141136
Created by admin on Mon Oct 21 22:49:43 UTC 2019 , Edited by admin on Mon Oct 21 22:49:43 UTC 2019
FDA ORPHAN DRUG 481015
Created by admin on Mon Oct 21 22:49:43 UTC 2019 , Edited by admin on Mon Oct 21 22:49:43 UTC 2019
WHO-ATC L01XE44
Created by admin on Mon Oct 21 22:49:43 UTC 2019 , Edited by admin on Mon Oct 21 22:49:43 UTC 2019
NCI_THESAURUS C129825
Created by admin on Mon Oct 21 22:49:43 UTC 2019 , Edited by admin on Mon Oct 21 22:49:43 UTC 2019
Code System Code Type Description
CAS
1454846-35-5
Created by admin on Mon Oct 21 22:49:43 UTC 2019 , Edited by admin on Mon Oct 21 22:49:43 UTC 2019
PRIMARY
NCI_THESAURUS
C113655
Created by admin on Mon Oct 21 22:49:43 UTC 2019 , Edited by admin on Mon Oct 21 22:49:43 UTC 2019
PRIMARY
INN
10278
Created by admin on Mon Oct 21 22:49:43 UTC 2019 , Edited by admin on Mon Oct 21 22:49:43 UTC 2019
PRIMARY
PUBCHEM
71731823
Created by admin on Mon Oct 21 22:49:43 UTC 2019 , Edited by admin on Mon Oct 21 22:49:43 UTC 2019
PRIMARY
ChEMBL
CHEMBL3286830
Created by admin on Mon Oct 21 22:49:43 UTC 2019 , Edited by admin on Mon Oct 21 22:49:43 UTC 2019
PRIMARY
EVMPD
SUB181272
Created by admin on Mon Oct 21 22:49:43 UTC 2019 , Edited by admin on Mon Oct 21 22:49:43 UTC 2019
PRIMARY
Related Record Type Details
TRANSPORTER -> INHIBITOR
METABOLIC ENZYME -> SUBSTRATE
MINOR
TRANSPORTER -> INHIBITOR
TRANSPORTER -> INHIBITOR
TRANSPORTER -> INHIBITOR
TARGET -> INHIBITOR
Ki
METABOLIC ENZYME -> SUBSTRATE
MAJOR
METABOLIC ENZYME -> SUBSTRATE
MAJOR
BINDER->LIGAND
In vitro, protein binding of lorlatinib to human plasma proteins, including serum albumin and ?1-acid glycoprotein, was 66% at a concentration of 2.4 ?M.
BINDING
TARGET -> INHIBITOR
INHIBITOR
IC50
METABOLIC ENZYME -> INDUCER
SALT/SOLVATE -> PARENT
TARGET -> INHIBITOR
IC50
TARGET -> INHIBITOR
Ki
TARGET -> INHIBITOR
Ki
TRANSPORTER -> INHIBITOR
TRANSPORTER -> INHIBITOR
METABOLIC ENZYME -> SUBSTRATE
MINOR
METABOLIC ENZYME -> INDUCER
ACTIVATOR
TARGET -> INHIBITOR
Ki
METABOLIC ENZYME -> SUBSTRATE
MINOR
TARGET -> INHIBITOR
Ki
TARGET -> INHIBITOR
Ki
METABOLIC ENZYME -> SUBSTRATE
MINOR
EXCRETED UNCHANGED
Following a single oral 100 mg dose of radiolabeled lorlatinib, 48% of the radioactivity was recovered in urine (< 1% as unchanged) and 41% in feces (about 9% as unchanged).
FECAL; URINE
TARGET -> INHIBITOR
Ki
METABOLIC ENZYME -> INHIBITOR
TIME-DEPENDENT INHIBITION
Ki
TARGET -> INHIBITOR
Ki
Related Record Type Details
METABOLITE INACTIVE -> PARENT
The benzoic acid metabolite of lorlatinib (PF-06895751) is pharmacologically inactive.
Related Record Type Details
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
Biological Half-life PHARMACOKINETIC SINGLE DOSE

ORAL

Blood-to-plasma ratio PHARMACOKINETIC
Tmax PHARMACOKINETIC SINGLE DOSE

ORAL

Biological Half-life PHARMACOKINETIC SINGLE DOSE

INTRAVENOUS

Volume of Distribution PHARMACOKINETIC SINGLE DOSE

INTRAVENOUS