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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:: 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

PubMed

PubMed

TitleDatePubMed
Isotype-specific Ras.GTP-levels predict the efficacy of farnesyl transferase inhibitors against human astrocytomas regardless of Ras mutational status.
2001 Jun 1
Synergy of the protein farnesyltransferase inhibitor SCH66336 and cisplatin in human cancer cell lines.
2001 May
Current status of clinical trials of farnesyltransferase inhibitors.
2001 Nov
An anion-induced regio- and chemoselective acylation and its application to the synthesis of an anticancer agent.
2001 Nov 15
Farnesyltransferase inhibitors.
2001 Oct
Agents targeting ras signaling pathway.
2002
Overcoming STI571 resistance with the farnesyl transferase inhibitor SCH66336.
2002 Aug 1
Inhibitors of farnesyl protein transferase and MEK1,2 induce apoptosis in fibroblasts transformed with farnesylated but not geranylgeranylated H-Ras.
2002 Feb 15
A phase II trial of farnesyl protein transferase inhibitor SCH 66336, given by twice-daily oral administration, in patients with metastatic colorectal cancer refractory to 5-fluorouracil and irinotecan.
2002 Jul
Phase I and pharmacological study of the oral farnesyltransferase inhibitor SCH 66336 given once daily to patients with advanced solid tumours.
2002 Nov
Farnesyl transferase inhibitors: a major breakthrough in anticancer therapy? Naples, 12 April 2002.
2002 Sep
Targeting RAS signalling pathways in cancer therapy.
2003 Jan
Trihalobenzocycloheptapyridine analogues of Sch 66336 as potent inhibitors of farnesyl protein transferase.
2003 Jan 2
Overcoming resistance to imatinib by combining targeted agents.
2003 Mar
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
Apoptotic synergism between STI571 and the farnesyl transferase inhibitor SCH66336 on an imatinib-sensitive cell line.
2003 Mar 1
Farnesyltransferase inhibitors--a novel approach in the treatment of advanced pancreatic carcinomas.
2003 Mar-Apr
Gateways to clinical trials.
2003 Nov
Farnesyltransferase inhibitors and their potential in the treatment of breast carcinoma.
2003 Oct
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
Solution phase parallel synthesis and evaluation of MAPK inhibitory activities of close structural analogues of a Ras pathway modulator.
2004 Aug 2
[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
Phase I study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in solid tumors.
2004 May 1
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 effect of the farnesyl protein transferase inhibitor SCH66336 on isoprenylation and signalling by the prostacyclin receptor.
2005 Feb 15
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
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
The synergistic combination of the farnesyl transferase inhibitor lonafarnib and paclitaxel enhances tubulin acetylation and requires a functional tubulin deacetylase.
2005 May 1
Farnesyltransferase inhibitor SCH-66336 downregulates secretion of matrix proteinases and inhibits carcinoma cell migration.
2005 May 1
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
[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
Gateways to clinical trials.
2006 Jul-Aug
Gateways to clinical trials.
2006 Mar
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
Farnesyl transferase inhibitors impair chromosomal maintenance in cell lines and human tumors by compromising CENP-E and CENP-F function.
2007 Apr
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
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
Farnesyl transferase inhibitor resistance probed by target mutagenesis.
2007 Sep 15
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