| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
H-ras (IC50 = 1.9 nM); K-ras (IC50 = 5.2 nM); N-ras (IC50 = 2.8 nM)[1]
|
|---|---|
| ln Vivo |
We have been developing a series of nonpeptidic, small molecule farnesyl protein transferase inhibitors that share a common tricyclic nucleus and compete with peptide/protein substrates for binding to farnesyl protein transferase. Here, we report on pharmacological and in vivo studies with SCH 66336, a lead compound in this structural class. SCH 66336 potently inhibits Ha-Ras processing in whole cells and blocks the transformed growth properties of fibroblasts and human tumor cell lines expressing activated Ki-Ras proteins. The anchorage-independent growth of many human tumor lines that lack an activated ras oncogene is also blocked by treatment with SCH 66336. In mouse, rat, and monkey systems, SCH 66336 has excellent oral bioavailability and pharmacokinetic properties. In the nude mouse, SCH 66336 demonstrated potent oral activity in a wide array of human tumor xenograft models including tumors of colon, lung, pancreas, prostate, and urinary bladder origin. Enhanced in vivo efficacy was observed when SCH 66336 was combined with various cytotoxic agents (cyclophosphamide, 5-fluorouracil, and vincristine). In a Ha-Ras transgenic mouse model, prophylactic treatment with SCH 66336 delayed tumor onset, reduced the average number of tumors/mouse, and reduced the average tumor weight/animal. In a therapeutic mode in which gavage treatment was initiated after the transgenic mice had developed palpable tumors, significant tumor regression was induced by SCH 66336 in a dose-dependent fashion. This was associated with increased apoptosis and decreased DNA synthesis in tumors of animals treated with SCH 66336. Enhanced efficacy was also observed in this model when SCH 66336 was combined with cyclophosphamide. SCH 66336 is presently being evaluated in Phase I clinical trials[1].
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| ADME/Pharmacokinetics |
Absorption
The absolute oral bioavailability of lonafarnib is unknown; in healthy subjects administration of either 75 or 100 mg of lonafarnib twice daily resulted in mean peak plasma concentrations (%CV) of 834 (32%) and 964 (32%) ng/mL, respectively. Twice daily administration of 115 mg/m2 lonafarnib in HGPS patients resulted in a median tmax of 2 hours (range 0-6), mean Cmax of 1777 ± 1083 ng/mL, mean AUC0-8hr of 9869 ± 6327 ng\*hr/mL, and a mean AUCtau of 12365 ± 9135 ng\*hr/mL. The corresponding values for a dose of 150 mg/m2 are: 4 hours (range 0-12), 2695 ± 1090 ng/mL, 16020 ± 4978 ng\*hr/mL, and 19539 ± 6434 ng\*hr/mL, respectively. Following a single oral dose of 75 mg in healthy subjects, the Cmax of lonafarnib decreased by 55% and 25%, and the AUC decreased by 29% and 21% for a high/low-fat meal compared to fasted conditions. Route of Elimination Up to 240 hours following oral administration of 104 mg [14C]-lonafarnib in fasted healthy subjects, approximately 62% and <1% of the initial radiolabeled dose was recovered in feces and urine, respectively. The two most prevalent metabolites were the active HM21 and HM17, which account for 14% and 15% of plasma radioactivity. Volume of Distribution In healthy patients administered either 75 or 100 mg lonafarnib twice daily, the steady-state apparent volumes of distribution were 97.4 L and 87.8 L, respectively. Metabolism / Metabolites Lonafarnib is metabolized _in vitro_ primarily by CYP3A4/5 and partially by CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1. Formation of the primary metabolites involves oxidation and subsequent dehydration in the pendant piperidine ring. Biological Half-Life Lonafarnib has a mean half-life of approximately 4-6 hours following oral administration of 100 mg twice daily in healthy subjects. |
| Toxicity/Toxicokinetics |
Hepatotoxicity
In the small prelicensure clinical trials conducted in children with progeria, serum aminotransferase elevations occurred in 35% of lonafarnib treated subjects but were usually mild and self-limited, rising to above 3 times the upper limit of normal (ULN) in only 5%. There were no liver related serious adverse events and no patient had a concurrent elevation in serum aminotransferase and bilirubin levels. Since approval of lonafarnib, there have been no published reports of drug induced liver injury associated with its use, although clinical experience with the drug, particularly with long term therapy, has been limited. Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury). Protein Binding Lonafarnib exhibits _in vitro_ plasma protein binding of ≥99% over a concentration range of 0.5-40.0 μg/mL. |
| References | |
| Additional Infomation |
4-{2-[4-(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 is a benzocycloheptapyridine that is benzo[5,6]cyclohepta[1,2-b]pyridine which is substituted at positions 3 and 10 by bromines, at position 8 by chlorine, and at position 11 by an N-acetylpiperidin-4-yl group in which one of the hydrogens of the acetyl moiety has been replaced by a 1-carbamoylpiperidin-4-yl group. It is a benzocycloheptapyridine, a N-acylpiperidine, a heteroarylpiperidine, an organochlorine compound, an organobromine compound and a member of ureas.
|
| Molecular Formula |
C27H31BR2CLN4O2
|
|---|---|
| Molecular Weight |
638.821644067764
|
| Exact Mass |
636.05
|
| Elemental Analysis |
C, 50.76; H, 4.89; Br, 25.02; Cl, 5.55; N, 8.77; O, 5.01
|
| CAS # |
193275-86-4
|
| Related CAS # |
Lonafarnib;193275-84-2
|
| PubChem CID |
9852353
|
| Appearance |
Typically exists as solid at room temperature
|
| Density |
1.5±0.1 g/cm3
|
| Boiling Point |
710.4±70.0 °C at 760 mmHg
|
| Flash Point |
383.5±35.7 °C
|
| Vapour Pressure |
0.0±2.3 mmHg at 25°C
|
| Index of Refraction |
1.630
|
| LogP |
5.03
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
3
|
| Rotatable Bond Count |
3
|
| Heavy Atom Count |
36
|
| Complexity |
790
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
BrC1=CC(=CC2CCC3=CC(=CN=C3[C@@H](C=21)C1CCN(C(CC2CCN(C(N)=O)CC2)=O)CC1)Br)Cl
|
| InChi Key |
DHMTURDWPRKSOA-UHFFFAOYSA-N
|
| InChi Code |
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)
|
| Chemical Name |
4-[2-[4-(6,15-dibromo-13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-yl)piperidin-1-yl]-2-oxoethyl]piperidine-1-carboxamide
|
| Synonyms |
Lonafarnib (Racemate); 193275-86-4; 4-{2-[4-(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; 4-(2-(4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo(5,6)cyclohepta(1,2-b)pyridin-11-yl)-1-piperidinyl)-2-oxoethyl)-1-piperidinecarboxamide; SCHEMBL94653; BDBM14433; CHEBI:90678; DTXSID90870198;
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
|
|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5654 mL | 7.8269 mL | 15.6539 mL | |
| 5 mM | 0.3131 mL | 1.5654 mL | 3.1308 mL | |
| 10 mM | 0.1565 mL | 0.7827 mL | 1.5654 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02527707 | Completed Has Results | Drug: lonafarnib Drug: Ritonavir |
Chronic Delta Hepatitis | Eiger BioPharmaceuticals | September 2015 | Phase 2 |
| NCT02579044 | Enrolling by invitation | Drug: Everolimus and lonafarnib | Progeria | Boston Children's Hospital | December 2015 | Phase 1 Phase 2 |
| NCT05229991 | Active, not recruiting | Drug: Lonafarnib Drug: Ritonavir |
Hepatitis D, Chronic | Soroka University Medical Center | May 15, 2021 | Phase 3 |
| NCT00773474 | Terminated Has Results | Drug: Lonafarnib | Metastatic Breast Cancer | George Sledge | October 2008 | Phase 2 |
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