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Chemical Structure| 177966-64-2 Chemical Structure| 177966-64-2

Structure of Fmoc-D-Phe(4-F)-OH
CAS No.: 177966-64-2

Chemical Structure| 177966-64-2

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Product Details of [ 177966-64-2 ]

CAS No. :177966-64-2
Formula : C24H20FNO4
M.W : 405.42
SMILES Code : O=C(O)[C@H](NC(OCC1C2=C(C3=C1C=CC=C3)C=CC=C2)=O)CC4=CC=C(F)C=C4
MDL No. :MFCD00235900
InChI Key :IXUMACXMEZBPJG-JOCHJYFZSA-N
Pubchem ID :16213164

Safety of [ 177966-64-2 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 177966-64-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 30
Num. arom. heavy atoms 18
Fraction Csp3 0.17
Num. rotatable bonds 8
Num. H-bond acceptors 5.0
Num. H-bond donors 2.0
Molar Refractivity 109.62
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

75.63 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

3.19
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

4.74
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

4.78
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

3.8
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

4.46
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

4.19

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-5.26
Solubility 0.00225 mg/ml ; 0.00000555 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-6.06
Solubility 0.000355 mg/ml ; 0.000000875 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Poorly soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-7.64
Solubility 0.00000924 mg/ml ; 0.0000000228 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Poorly soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

No
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

Yes
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

Yes
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

Yes
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-5.41 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

0.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.56

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<3.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

3.97

Application In Synthesis of [ 177966-64-2 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 177966-64-2 ]

[ 177966-64-2 ] Synthesis Path-Downstream   1~1

  • 1
  • [ 177966-64-2 ]
  • [ 71989-31-6 ]
  • [ 35737-15-6 ]
  • [ 64-19-7 ]
  • [ 133464-46-7 ]
  • Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
  • [ 147290-11-7 ]
  • Ac-Arg-cyclo(Glu-Pro-D-Phe(4-F)-Arg-Trp-Orn)-NH<SUB>2</SUB> [ No CAS ]
YieldReaction ConditionsOperation in experiment
16% 6.1 Specific Peptides. (0263) Peptides of the following structures were synthesized by the general methods described above, and except where indicated MC1-R Ki and MC4-R Ki values for each peptide were determined in competitive binding assays using [I125]-NDP-alpha-MSH as described in 7.1 below. All peptides were prepared in the TFA acid salt form, except for the peptides of Examples 43, 46 and 67, which were prepared in the acetate salt form. (0264) The syntheses of some specific peptides of the invention are illustrated below. These peptides were prepared using solid phase peptide synthesis by means of a Symphony Multiplex Peptide Synthesizer (Rainin Instrument Company/Protein Technologies Inc) automated peptide synthesizer. Step 1: Coupling of Orn (0265) The Sierber resin 9-Fmoc-Aminoxanthen-3-yloxy-polystyrene resin (0.39 mol/g, ChemPep Inc., 151902) was swelled in 3×5 mL of DMF for 10 min. Thereafter, Fmoc was deprotected using 2×5 mL of 20% piperidine in DMF for 10 min. The resin was then washed in 6×5 mL DMF for 30 sec. 5 mL of 200 mM <strong>[147290-11-7]<strong>[147290-11-7]Fmoc-Orn(Alloc)</strong>-OH</strong> in DMF and 5 mL 200 mM HBTU containing 400 mM NMM in DMF was added and after 30 min the resin was washed with 3×5 mL DMF for 30 sec. Step 2: Coupling of Next 6 Amino Acids (AA) (0266) The resin from step 1 was first swelled in 3×5 mL of DMF for 30 sec, Fmoc was deprotected using 2×5 mL of 20% piperidine in DMF for 10 min and then washed with 6×5 mL DMF for 30 sec. 5 mL of 200 mM Fmoc-AA-OH solution and 5 mL 200 mM HBTU containing 400 mM NMM in DMF was added and after 30 min the resin was washed with 3×5 mL DMF for 30 sec. (0267) This step was repeated for each amino acid (AA). Step 3: Acetylation (0268) Fmoc was deprotected using 2×5 mL of 20% piperidine in DMF for 10 min and the resin was then washed with 3×5 mL DMF for 30 sec. Thereafter, 5 mL of 50% Ac2O/DMF solution was added and after 30 min the peptide resin was washed with 3×5 mL DMF for 30 sec and 6×5 mL DCM for 30 sec. Step 4: Allyl/Alloc Deprotection (0269) The peptide resin (0.6 mmol) was mixed with phenylsilane (Oakwood Chemical, S13600) (20 eq.) in 20 mL of DCM and bubbled with nitrogen for 5 min. (0270) Tetrakis(triphenylphosphine)-palladium(0) (Strem Chemicals, Inc., 46-2150) (0.2 eq.) was added and the mixture was agitated with nitrogen for 1 hour. The procedure was repeated one time for 1 hour and an additional time for 30 min with fresh reagents. The treated peptide resin was then washed with DCM x 3 and DMF x 3. Step 5: Lactam Formation (0271) The lactam ring was formed on the peptide resin using TBTU (2 eq.) and ethyldiisopropylamine (DIEA) (4 eq.) in 20 mL DMF for 1 hour. A second coupling may be needed if a positive Kaiser Ninhydrin test is observed. Step 6: Peptide Cleavage (0272) The peptide resin (0.6 mmol) was mixed with 20 mL of 5% sodium diethyldithio-carbamate trihydrate (NaCS2NEt2, Aldrich, 228680) in DMF for 20 min and then washed with DMF×3, DCM×3 and diethyl ether×2. (0273) The resin (0.6 mmol) was then stirred in a 25 mL of TFA/TIS/H2O (90:5.0:5.0 v/v/v) for 2.5 hours. The resin was filtered. The filtrate was concentrated to about 10 mL in volume and about 140 mL of cold diethyl ether (pre-cooled to about 0 C.) was added. (0274) The mixture was vortexed, and then placed in the refrigerator (about -4 C.) for 1 h, centrifuged for 5 min at 2800 rpm, and the ether layer was decanted. (0275) The peptide was washed with 90 mL of cold diethyl ether (pre-cooled to about 0 C.), vortexed, centrifuged for 5 min at 2800 rpm, and ether layer decanted. (0276) The resulting solid was dissolved in 50% AcOH/H2O and stored at room temperature overnight. (0277) The crude peptide solution was concentrated to afford solid crude peptide for HPLC purification. (0278) After HPLC purification, the peptide TFA salt was converted to peptide acetate salt using ion exchange (×100 eq.). The anion exchange resin used was Dowex SBR LC NG, OH-form (Supelco, Cat14036-U). Example 67 (0284) [table-us-00009-en] (SEQIDNO:72) Ac-Arg-cyclo(Glu-Pro-D-Phe(4-F)-Arg-Trp-Orn)-NH2 (0285) The procedure described above was followed in the preparation of the title peptide except for that 15 mL of 5% sodium diethyldithio-carbamate trihydrate in DMF, 16 mL of TFA/TIS/H2O and 90 mL+60 mL of diethyl ether were used in step 6. Moreover, the filtrate was concentrated to 5 mL. (0286) The amino acids added in step 2 were, in the order of being coupled, Fmoc-Trp(Boc)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-D-Phe(4-F)-OH, Fmoc-Pro-OH, Fmoc-Glu(OAll)-OH, and Fmoc-Arg(Pbf)-OH. (0287) The resulting peptide was purified by HPLC (column: Atlantis dC18 OBD 19×100 mm (5mu., Waters part 186001367) using 10% MeOH/H2O containing 0.1% TFA (solvent A) and 90% MeOH/H2O containing 0.1% TFA (solvent B). A gradient of 5%-10% of solvent B for 5 min and 10%-40% of solvent B for 30 min was used. (0288) The peptide yield was 16%.
 

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