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Details

Stereochemistry ABSOLUTE
Molecular Formula C27H31Br2ClN4O2
Molecular Weight 638.822
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of LONAFARNIB

SMILES

NC(=O)N1CCC(CC(=O)N2CCC(CC2)[C@H]3C4=C(CCC5=C3C(Br)=CC(Cl)=C5)C=C(Br)C=N4)CC1

InChI

InChIKey=DHMTURDWPRKSOA-RUZDIDTESA-N
InChI=1S/C27H31Br2ClN4O2/c28-20-12-19-2-1-18-13-21(30)14-22(29)24(18)25(26(19)32-15-20)17-5-9-33(10-6-17)23(35)11-16-3-7-34(8-4-16)27(31)36/h12-17,25H,1-11H2,(H2,31,36)/t25-/m1/s1

HIDE SMILES / InChI
Molecular Formula C27H31Br2ClN4O2
Molecular Weight 638.822
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 1 / 1
E/Z Centers 0
Optical Activity UNSPECIFIED

Description
Curator's Comment: description was created based on several sources, including: https://www.ncbi.nlm.nih.gov/pubmed/22620979 http://www.eigerbio.com/hepatitis-d/about-lonafarnib/

Lonafarnib is a well-characterized, late-stage, orally active inhibitor of farnesyl transferase, an enzyme involved in modification of proteins through a process called prenylation. It is Investigated for use/treatment in Progeria, Cancer, Hepatitis D. Lonafarnib completely inhibits Rheb prenylation and phosphorylation of S6 ribosomal protein in cell culture, indicating a lack of alternative Rheb prenylation. Other groups have demonstrated that inhibition of protein synthesis via inactivation of eukaryotic elongation factor (eEF2) could be an alternate mechanism of lonafarnib induced growth inhibition that is independent of RAS/p70S6K eEF. Adverse effects included fatigue, diarrhea, dyspnea and neutropenia and respiratory insufficiency.

CNS Activity

CNS Penetrant
2432
Curator's Comment: The results indicated that lonafarnib appeared to be well-tolerated, able to cross blood-brain barrier and to show modest antitumor effects.

Originator

Approval Year

2020
842
Targets

Targets

Primary TargetPharmacologyConditionPotency
Inhibitor
8146
 1.9 nM [IC50]
Inhibitor
8146
 50000.0 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Phase II
1133
Unknown

Approved Use

Unknown
Primary
Phase II
1133
Unknown

Approved Use

Unknown
Primary
Phase II
1133
Unknown

Approved Use

Unknown
PubMed

PubMed

TitleDatePubMed
Phase I and pharmacokinetic study of the oral farnesyl transferase inhibitor SCH 66336 given twice daily to patients with advanced solid tumors.
2001 Feb 15
Synergy of the protein farnesyltransferase inhibitor SCH66336 and cisplatin in human cancer cell lines.
2001 May
Farnesyl protein transferase inhibition: a novel approach to anti-tumor therapy. the discovery and development of SCH 66336.
2001 Oct
Exploring the role of bromine at C(10) of (+)-4-[2-[4-(8-chloro-3,10-dibromo- 6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(R)-yl)-1-piperidinyl]-2- oxoethyl]-1-piperidinecarboxamide (Sch-66336): the discovery of indolocycloheptapyridine inhibitors of farnesyl protein transferase.
2002 Aug 29
Gateways to clinical trials.
2002 Jul-Aug
Farnesyl transferase inhibitors as anticancer agents.
2002 Sep
The farnesyl protein transferase inhibitor lonafarnib (SCH66336) is an inhibitor of multidrug resistance proteins 1 and 2.
2003 Dec
Targeting RAS signalling pathways in cancer therapy.
2003 Jan
Farnesyl transferase inhibitors in clinical development.
2003 Jun
Efficacy of SCH66336, a farnesyl transferase inhibitor, in conjunction with imatinib against BCR-ABL-positive cells.
2003 Mar
Farnesyl transferase inhibitors in the treatment of breast cancer.
2003 Mar
Gateways to clinical trials.
2003 Nov
[Ras signaling pathway as a target for farnesyltransferase inhibitors--a new, promising prospects in the treatment for malignant disorders].
2004
New targets for therapy in breast cancer: farnesyltransferase inhibitors.
2004
Solution phase parallel synthesis and evaluation of MAPK inhibitory activities of close structural analogues of a Ras pathway modulator.
2004 Aug 2
Synthesis of 5-bromopyridyl-2-magnesium chloride and its application in the synthesis of functionalized pyridines.
2004 Dec 23
In vitro study of farnesyltransferase inhibitor SCH 66336, in combination with chemotherapy and radiation, in non-small cell lung cancer cell lines.
2004 Feb
[Molecular pathogenesis of chronic myeloid leukemia and tyrosine kinase inhibitor].
2004 Jan
Cancer treatment with kinase inhibitors: what have we learnt from imatinib?
2004 Jan 12
Gateways to clinical trials.
2004 Mar
Farnesyltransferase inhibition: who are the Aktors?
2004 Nov
The farnesyltransferase inhibitor Lonafarnib induces growth arrest or apoptosis of human lung cancer cells without downregulation of Akt.
2004 Nov
Gateways to clinical trials.
2004 Sep
Phase II study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in patients with taxane-refractory/resistant nonsmall cell lung carcinoma.
2005 Aug 1
The combination of the farnesyl transferase inhibitor lonafarnib and the proteasome inhibitor bortezomib induces synergistic apoptosis in human myeloma cells that is associated with down-regulation of p-AKT.
2005 Dec 15
Lonafarnib reduces the resistance of primitive quiescent CML cells to imatinib mesylate in vitro.
2005 Jul
Multicentre EORTC study 16997: feasibility and phase II trial of farnesyl transferase inhibitor & gemcitabine combination in salvage treatment of advanced urothelial tract cancers.
2005 May
The synergistic combination of the farnesyl transferase inhibitor lonafarnib and paclitaxel enhances tubulin acetylation and requires a functional tubulin deacetylase.
2005 May 1
A multinomial Phase II study of lonafarnib (SCH 66336) in patients with refractory urothelial cancer.
2005 May-Jun
Development of farnesyl transferase inhibitors: a review.
2005 Sep
Hypoxia-inducible factor 1alpha and antiangiogenic activity of farnesyltransferase inhibitor SCH66336 in human aerodigestive tract cancer.
2005 Sep 7
Gateways to clinical trials.
2006 Mar
Combination therapy with aromatase inhibitors: the next era of breast cancer treatment?
2006 Sep 18
Farnesyl transferase inhibitors impair chromosomal maintenance in cell lines and human tumors by compromising CENP-E and CENP-F function.
2007 Apr
Phase I and pharmacokinetic study of the oral farnesyltransferase inhibitor lonafarnib administered twice daily to pediatric patients with advanced central nervous system tumors using a modified continuous reassessment method: a Pediatric Brain Tumor Consortium Study.
2007 Jul 20
The farnesyltransferase inhibitor lonafarnib induces CCAAT/enhancer-binding protein homologous protein-dependent expression of death receptor 5, leading to induction of apoptosis in human cancer cells.
2007 Jun 29
New agents for treatment of advanced transitional cell carcinoma.
2007 May
Farnesyltransferase inhibitors inhibit T-cell cytokine production at the posttranscriptional level.
2007 Sep 15
Farnesyl transferase inhibitor resistance probed by target mutagenesis.
2007 Sep 15
Exploring three-dimensional quantitative structural activity relationship (3D-QSAR) analysis of SCH 66336 (Sarasar) analogues of farnesyltransferase inhibitors.
2008 Jan
Patents

Patents

US 5874442
1
WO 9723478
1

Sample Use Guides

In Vivo Use Guide
150 mg/m2 by mouth twice daily
Route of Administration: Oral
In Vitro Use Guide
Several experiments with 1 µM SCH66336 resulted in an average 70% reduction in S6 phosphorylation.
Substance Class Chemical
Created
by admin
on Sat Dec 17 17:09:23 UTC 2022
Edited
by admin
on Sat Dec 17 17:09:23 UTC 2022
Record UNII
IOW153004F
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
LONAFARNIB
INN   MI   USAN   WHO-DD  
INN   USAN  
Official Name English
SCH-66336
Code English
SARASAR
Brand Name English
SCH66336
Code English
LONAFARNIB [MI]
Common Name English
SCH 66336
Code English
1-PIPERIDINECARBOXAMIDE, 4-(2-(4-((11R-3,10-DIBROMO-8-CHLORO-6,11-DIHYDRO-5H-BENZO(5,6)CYCLOHEPTA(1,2-B)PYRIDIN-11-YL)-1-PIPERIDINYL)-2-OXOETHYL)-
Common Name English
LONAFARNIB [ORANGE BOOK]
Common Name English
ZOKINVY
Brand Name English
LONAFARNIB [USAN]
Common Name English
(+)-4-(2-(4-(11R)-3,10-DIBROMO-8-CHLORO-6,11-DIHYDRO-5H-BENZO(5,6)CYCLOHEPTA(1,2-B)PYRIDIN-11-YL)-PIPERIDIN-1-YL))-2-OXOETHYL)-PIPERIDINE-1-CARBOXAMIDE
Common Name English
Lonafarnib [WHO-DD]
Common Name English
lonafarnib [INN]
Common Name English
Classification Tree Code System Code
FDA ORPHAN DRUG 411713
Created by admin on Sat Dec 17 17:09:23 UTC 2022 , Edited by admin on Sat Dec 17 17:09:23 UTC 2022
FDA ORPHAN DRUG 333411
Created by admin on Sat Dec 17 17:09:23 UTC 2022 , Edited by admin on Sat Dec 17 17:09:23 UTC 2022
EU-Orphan Drug EU/3/18/2118
Created by admin on Sat Dec 17 17:09:23 UTC 2022 , Edited by admin on Sat Dec 17 17:09:23 UTC 2022
NCI_THESAURUS C2020
Created by admin on Sat Dec 17 17:09:23 UTC 2022 , Edited by admin on Sat Dec 17 17:09:23 UTC 2022
Code System Code Type Description
WIKIPEDIA
LONAFARNIB
Created by admin on Sat Dec 17 17:09:23 UTC 2022 , Edited by admin on Sat Dec 17 17:09:23 UTC 2022
PRIMARY
PUBCHEM
148195
Created by admin on Sat Dec 17 17:09:23 UTC 2022 , Edited by admin on Sat Dec 17 17:09:23 UTC 2022
PRIMARY
NCI_THESAURUS
C1829
Created by admin on Sat Dec 17 17:09:23 UTC 2022 , Edited by admin on Sat Dec 17 17:09:23 UTC 2022
PRIMARY
EPA CompTox
DTXSID90172927
Created by admin on Sat Dec 17 17:09:23 UTC 2022 , Edited by admin on Sat Dec 17 17:09:23 UTC 2022
PRIMARY
CAS
193275-84-2
Created by admin on Sat Dec 17 17:09:23 UTC 2022 , Edited by admin on Sat Dec 17 17:09:23 UTC 2022
PRIMARY
MERCK INDEX
M6892
Created by admin on Sat Dec 17 17:09:23 UTC 2022 , Edited by admin on Sat Dec 17 17:09:23 UTC 2022
PRIMARY Merck Index
FDA UNII
IOW153004F
Created by admin on Sat Dec 17 17:09:23 UTC 2022 , Edited by admin on Sat Dec 17 17:09:23 UTC 2022
PRIMARY
RXCUI
2467553
Created by admin on Sat Dec 17 17:09:23 UTC 2022 , Edited by admin on Sat Dec 17 17:09:23 UTC 2022
PRIMARY
USAN
MM-63
Created by admin on Sat Dec 17 17:09:23 UTC 2022 , Edited by admin on Sat Dec 17 17:09:23 UTC 2022
PRIMARY
MESH
C115354
Created by admin on Sat Dec 17 17:09:23 UTC 2022 , Edited by admin on Sat Dec 17 17:09:23 UTC 2022
PRIMARY
EVMPD
SUB21038
Created by admin on Sat Dec 17 17:09:23 UTC 2022 , Edited by admin on Sat Dec 17 17:09:23 UTC 2022
PRIMARY
DAILYMED
IOW153004F
Created by admin on Sat Dec 17 17:09:23 UTC 2022 , Edited by admin on Sat Dec 17 17:09:23 UTC 2022
PRIMARY
ChEMBL
CHEMBL298734
Created by admin on Sat Dec 17 17:09:23 UTC 2022 , Edited by admin on Sat Dec 17 17:09:23 UTC 2022
PRIMARY
DRUG BANK
DB06448
Created by admin on Sat Dec 17 17:09:23 UTC 2022 , Edited by admin on Sat Dec 17 17:09:23 UTC 2022
PRIMARY
CHEBI
47097
Created by admin on Sat Dec 17 17:09:23 UTC 2022 , Edited by admin on Sat Dec 17 17:09:23 UTC 2022
PRIMARY
INN
8191
Created by admin on Sat Dec 17 17:09:23 UTC 2022 , Edited by admin on Sat Dec 17 17:09:23 UTC 2022
PRIMARY
Related Record Type Details
CYTOCHROME P450 3A5
METABOLIC ENZYME -> SUBSTRATE
CYTOCHROME P450 3A4
METABOLIC ENZYME -> INHIBITOR
Lonafarnib is a potent CYP3A time-dependent and mechanism-based inhibitor.
TIME-DEPENDENT INHIBITION
POTENCY
OATP1B1
TRANSPORTER -> INHIBITOR
CYTOCHROME P450 1A2
METABOLIC ENZYME -> SUBSTRATE
IN VITRO
CYTOCHROME P450 2C8
METABOLIC ENZYME -> SUBSTRATE
ATP-BINDING CASSETTE SUB-FAMILY G MEMBER 2
TRANSPORTER -> INHIBITOR
MULTIDRUG RESISTANCE PROTEIN 1
TRANSPORTER -> SUBSTRATE
Lonafarnib is likely a marginal substrate of P-gp.
FARNESYLTRANSFERASE
TARGET -> INHIBITOR
CYTOCHROME P450 2C9
METABOLIC ENZYME -> SUBSTRATE
IN VITRO
CYTOCHROME P450 2C19
METABOLIC ENZYME -> SUBSTRATE
IN VITRO
CYTOCHROME P450 2E1
METABOLIC ENZYME -> SUBSTRATE
IN VITRO
CYTOCHROME P450 2C8
METABOLIC ENZYME -> INHIBITOR
CYTOCHROME P450 2A6
METABOLIC ENZYME -> SUBSTRATE
IN VITRO
CYTOCHROME P450 2C19
METABOLIC ENZYME -> INHIBITOR
PLASMA PROTEIN FRACTION (HUMAN)
BINDER->LIGAND
In vitro plasma protein binding of lonafarnib was greater than or equal to 99% over the concentration range between 0.5 to 40.0 ?g/mL.
MULTIDRUG RESISTANCE PROTEIN 1
TRANSPORTER -> INHIBITOR
OATP-8
TRANSPORTER -> INHIBITOR
CYTOCHROME P450 3A4
METABOLIC ENZYME -> SUBSTRATE
MAJOR
Related Record Type Details
Structure of 2-HYDROXY-LONAFARNIB, (1-PIPERIDINECARBOXAMIDE RING)
METABOLITE -> PARENT
Structure of 1(2H)-PYRIDINECARBOXAMIDE, 4-(2-(4-((11R)-3,10-DIBROMO-8-CHLORO-6,11-DIHYDRO-5H-BENZO(5,6)CYCLOHEPTA(1,2-B)PYRIDIN-11-YL)-1-PIPERIDINYL)-2-OXOETHYL)-3,4-DIHYDRO-
METABOLITE -> PARENT
Related Record Type Details
Structure of LONAFARNIB
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
Volume of Distribution PHARMACOKINETIC IN HEALTHY SUBJECTS

ORAL ADMINISTRATION DOSE

AT STEADY-STATE

Tmax PHARMACOKINETIC AT STEADY-STATE

DOSE

ORAL ADMINISTRATION TWICE DAILY

Volume of Distribution PHARMACOKINETIC AT STEADY-STATE

ORAL ADMINISTRATION TWICE DAILY

IN HEALTHY SUBJECTS

Biological Half-life PHARMACOKINETIC IN HEALTHY SUBJECTS

ORAL ADMINISTRATION TWICE DAILY

Tmax PHARMACOKINETIC ORAL ADMINISTRATION TWICE DAILY

AT STEADY-STATE

DOSE

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