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Details

Stereochemistry ABSOLUTE
Molecular Formula C27H31Br2ClN4O2
Molecular Weight 638.8216
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of LONAFARNIB

SMILES

C1Cc2cc(cnc2[C@]([H])(C3CCN(CC3)C(=O)CC4CCN(CC4)C(=N)O)c5c1cc(cc5Br)Cl)Br

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 638.8216
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

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.

Approval Year

Targets

Targets

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

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
PubMed

PubMed

TitleDatePubMed
[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
Novel agents and incremental advances in the treatment of head and neck cancer.
2004 Apr
Synthesis of 5-bromopyridyl-2-magnesium chloride and its application in the synthesis of functionalized pyridines.
2004 Dec 23
Farnesyltransferase inhibitors as anticancer agents: critical crossroads.
2004 Jul
Phase I study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in solid tumors.
2004 May 1
Farnesyltransferase inhibition: who are the Aktors?
2004 Nov
Clinical activity of farnesyl transferase inhibitors in hematologic malignancies: possible mechanisms of action.
2004 Nov
The farnesyltransferase inhibitor Lonafarnib induces growth arrest or apoptosis of human lung cancer cells without downregulation of Akt.
2004 Nov
Effects of insulin-like growth factor binding protein-3 and farnesyltransferase inhibitor SCH66336 on Akt expression and apoptosis in non-small-cell lung cancer cells.
2004 Oct 20
Gateways to clinical trials.
2004 Sep
Quantitative analysis of the farnesyl transferase inhibitor lonafarnib (Sarasartrade mark, SCH66336) in human plasma using high-performance liquid chromatography coupled with tandem mass spectrometry.
2005
Phase II study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in patients with taxane-refractory/resistant nonsmall cell lung carcinoma.
2005 Aug 1
Microtubule interactions with chemically diverse stabilizing agents: thermodynamics of binding to the paclitaxel site predicts cytotoxicity.
2005 Dec
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
Hyperleukocytosis complicating lonafarnib treatment in patients with chronic myelomonocytic leukemia.
2005 Feb
The effect of the farnesyl protein transferase inhibitor SCH66336 on isoprenylation and signalling by the prostacyclin receptor.
2005 Feb 15
Lonafarnib reduces the resistance of primitive quiescent CML cells to imatinib mesylate in vitro.
2005 Jul
Farnesyltransferase inhibitor SCH66336 induces rapid phosphorylation of eukaryotic translation elongation factor 2 in head and neck squamous cell carcinoma cells.
2005 Jul 1
Gateways to clinical trials.
2005 Mar
Hit to Lead Success Stories--IBC Conference: Effective chemistry strategies for reducing attrition rates and speeding lead compounds into the pipeline. 31 January-1 February 2005, San Diego, CA, USA.
2005 Mar
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
Farnesyltransferase inhibitors in myelodysplastic syndrome.
2005 May
Isoprenylation of intracellular proteins as a new target for the therapy of human neoplasms: preclinical and clinical implications.
2005 May
Farnesyltransferase inhibitor SCH-66336 downregulates secretion of matrix proteinases and inhibits carcinoma cell migration.
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
The farnesyl transferase inhibitor (FTI) SCH66336 (lonafarnib) inhibits Rheb farnesylation and mTOR signaling. Role in FTI enhancement of taxane and tamoxifen anti-tumor activity.
2005 Sep 2
Hypoxia-inducible factor 1alpha and antiangiogenic activity of farnesyltransferase inhibitor SCH66336 in human aerodigestive tract cancer.
2005 Sep 7
Myelodysplasia: when to treat and how.
2006
[Farnesyl transferase inhibitors--a novel agent for breast cancer].
2006 Apr
Identification of human liver cytochrome P450 enzymes responsible for the metabolism of lonafarnib (Sarasar).
2006 Apr
A generalized response surface model with varying relative potency for assessing drug interaction.
2006 Dec
Identification of insulin-like growth factor binding protein-3 as a farnesyl transferase inhibitor SCH66336-induced negative regulator of angiogenesis in head and neck squamous cell carcinoma.
2006 Jan 15
Gateways to clinical trials.
2006 Jul-Aug
Lonafarnib in cancer therapy.
2006 Jun
Identification of unstable metabolites of Lonafarnib using liquid chromatography-quadrupole time-of-flight mass spectrometry, stable isotope incorporation and ion source temperature alteration.
2006 Nov
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
The farnesyl transferase inhibitor, tipifarnib, is a potent inhibitor of the MDR1 gene product, P-glycoprotein, and demonstrates significant cytotoxic synergism against human leukemia cell lines.
2007 Apr
Phase I study of the farnesyltransferase inhibitor lonafarnib with weekly paclitaxel in patients with solid tumors.
2007 Jan 15
Farnesyltransferase inihibitors in hematologic malignancies.
2007 Jul
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
Inhibitors of the mevalonate pathway as potential therapeutic agents in multiple myeloma.
2007 Mar
New agents for treatment of advanced transitional cell carcinoma.
2007 May
Phase 1 study of lonafarnib (SCH 66336) and imatinib mesylate in patients with chronic myeloid leukemia who have failed prior single-agent therapy with imatinib.
2007 Sep 15
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

Sample Use Guides

150 mg/m2 by mouth twice daily
Route of Administration: Oral
Several experiments with 1 µM SCH66336 resulted in an average 70% reduction in S6 phosphorylation.
Substance Class Chemical
Created
by admin
on Sat Jun 26 14:18:16 UTC 2021
Edited
by admin
on Sat Jun 26 14:18:16 UTC 2021
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 [WHO-DD]
Common Name 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
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 [INN]
Common Name English
Classification Tree Code System Code
FDA ORPHAN DRUG 411713
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
FDA ORPHAN DRUG 333411
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
EU-Orphan Drug EU/3/18/2118
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
NCI_THESAURUS C2020
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
Code System Code Type Description
WIKIPEDIA
LONAFARNIB
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
PRIMARY
PUBCHEM
148195
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
PRIMARY
NCI_THESAURUS
C1829
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
PRIMARY
EPA CompTox
193275-84-2
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
PRIMARY
CAS
193275-84-2
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
PRIMARY
MERCK INDEX
M6892
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
PRIMARY Merck Index
FDA UNII
IOW153004F
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
PRIMARY
MESH
C115354
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
PRIMARY
EVMPD
SUB21038
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
PRIMARY
ChEMBL
CHEMBL298734
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
PRIMARY
DRUG BANK
DB06448
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
PRIMARY
INN
8191
Created by admin on Sat Jun 26 14:18:17 UTC 2021 , Edited by admin on Sat Jun 26 14:18:17 UTC 2021
PRIMARY
Related Record Type Details
METABOLIC ENZYME -> SUBSTRATE
METABOLIC ENZYME -> INHIBITOR
Lonafarnib is a potent CYP3A time-dependent and mechanism-based inhibitor.
TIME-DEPENDENT INHIBITION
POTENCY
TRANSPORTER -> INHIBITOR
METABOLIC ENZYME -> SUBSTRATE
IN VITRO
METABOLIC ENZYME -> SUBSTRATE
TRANSPORTER -> INHIBITOR
TRANSPORTER -> SUBSTRATE
Lonafarnib is likely a marginal substrate of P-gp.
METABOLIC ENZYME -> SUBSTRATE
IN VITRO
METABOLIC ENZYME -> SUBSTRATE
IN VITRO
METABOLIC ENZYME -> SUBSTRATE
IN VITRO
METABOLIC ENZYME -> INHIBITOR
METABOLIC ENZYME -> SUBSTRATE
IN VITRO
METABOLIC ENZYME -> INHIBITOR
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.
TRANSPORTER -> INHIBITOR
TRANSPORTER -> INHIBITOR
METABOLIC ENZYME -> SUBSTRATE
MAJOR
Related Record Type Details
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