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
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
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 |
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
Sample Use Guides
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
Edited
Mon Oct 21 22:49:43 UTC 2019
by
admin
on
Mon Oct 21 22:49:43 UTC 2019
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Record UNII |
OSP71S83EU
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Record Status |
Validated (UNII)
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Record Version |
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Official Name | English | ||
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Brand Name | English | ||
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Common Name | English | ||
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Code | English | ||
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Common Name | English | ||
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Systematic Name | English | ||
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Common Name | English | ||
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Systematic Name | English |
Classification Tree | Code System | Code | ||
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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
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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
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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
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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
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Code System | Code | Type | Description | ||
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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
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PRIMARY | |||
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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
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PRIMARY | |||
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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
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PRIMARY | |||
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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
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PRIMARY | |||
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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
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PRIMARY | |||
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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
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PRIMARY |
Related Record | Type | Details | ||
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TRANSPORTER -> INHIBITOR | |||
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METABOLIC ENZYME -> SUBSTRATE |
MINOR
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TRANSPORTER -> INHIBITOR | |||
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TRANSPORTER -> INHIBITOR | |||
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TRANSPORTER -> INHIBITOR | |||
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TARGET -> INHIBITOR |
Ki
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METABOLIC ENZYME -> SUBSTRATE |
MAJOR
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METABOLIC ENZYME -> SUBSTRATE |
MAJOR
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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
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TARGET -> INHIBITOR |
INHIBITOR
IC50
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METABOLIC ENZYME -> INDUCER |
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SALT/SOLVATE -> PARENT | |||
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TARGET -> INHIBITOR |
IC50
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TARGET -> INHIBITOR |
Ki
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TARGET -> INHIBITOR |
Ki
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TRANSPORTER -> INHIBITOR | |||
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TRANSPORTER -> INHIBITOR | |||
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METABOLIC ENZYME -> SUBSTRATE |
MINOR
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METABOLIC ENZYME -> INDUCER |
ACTIVATOR
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TARGET -> INHIBITOR |
Ki
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METABOLIC ENZYME -> SUBSTRATE |
MINOR
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TARGET -> INHIBITOR |
Ki
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TARGET -> INHIBITOR |
Ki
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METABOLIC ENZYME -> SUBSTRATE |
MINOR
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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
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TARGET -> INHIBITOR |
Ki
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METABOLIC ENZYME -> INHIBITOR |
TIME-DEPENDENT INHIBITION
Ki
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TARGET -> INHIBITOR |
Ki
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Related Record | Type | Details | ||
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METABOLITE INACTIVE -> PARENT |
The benzoic acid metabolite of lorlatinib (PF-06895751) is pharmacologically inactive.
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Related Record | Type | Details | ||
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ACTIVE MOIETY |
Name | Property Type | Amount | Referenced Substance | Defining | Parameters | References |
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Biological Half-life | PHARMACOKINETIC |
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SINGLE DOSE |
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Blood-to-plasma ratio | PHARMACOKINETIC |
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Tmax | PHARMACOKINETIC |
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SINGLE DOSE |
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Biological Half-life | PHARMACOKINETIC |
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SINGLE DOSE |
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Volume of Distribution | PHARMACOKINETIC |
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SINGLE DOSE |
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