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Chemical Structure| 154775-43-6 Chemical Structure| 154775-43-6

Structure of 154775-43-6

Chemical Structure| 154775-43-6

3-(1-(tert-Butoxycarbonyl)piperidin-4-yl)propanoic acid

CAS No.: 154775-43-6

4.5 *For Research Use Only !

Cat. No.: A194868 Purity: 97%

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Product Citations

Product Citations

Rathje, Oliver H. ; Perryman, Lara ; Payne, Richard J. ; Hamprecht, Dieter W. ;

Abstract: Mixed Lineage Kinase domain-Like pseudokinase (MLKL) is implicated in a broad range of diseases due to its role as the ultimate effector of necroptosis and has therefore emerged as an attractive drug target. Here, we describe the development of PROteolysis TArgeting Chimeras (PROTACs) as a novel approach to knock down MLKL through chem. means. A series of candidate degraders were synthesized from a high-affinity pyrazole carboxamide-based MLKL ligand leading to the identification of a PROTAC mol. that effectively degraded MLKL and completely abrogated cell death in a TSZ model of necroptosis. By leveraging the innate ability of these PROTACs to degrade MLKL in a dose-dependent manner, the quant. relationship between MLKL levels and necroptosis was interrogated. This work demonstrates the feasibility of targeting MLKL using a PROTAC approach and provides a powerful tool to further our understanding of the role of MLKL within the necroptotic pathway.

Alternative Products

Product Details of [ 154775-43-6 ]

CAS No. :154775-43-6
Formula : C13H23NO4
M.W : 257.33
SMILES Code : O=C(O)CCC1CCN(C(OC(C)(C)C)=O)CC1
MDL No. :MFCD01861212
InChI Key :XWZDPNBLQJCKNC-UHFFFAOYSA-N
Pubchem ID :1512540

Safety of [ 154775-43-6 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P261-P280-P305+P351+P338

Computational Chemistry of [ 154775-43-6 ] Show Less

Physicochemical Properties

Num. heavy atoms 18
Num. arom. heavy atoms 0
Fraction Csp3 0.85
Num. rotatable bonds 6
Num. H-bond acceptors 4.0
Num. H-bond donors 1.0
Molar Refractivity 72.79
TPSA ?

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

66.84 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.61
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

1.71
Log Po/w (WLOGP)?

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

2.12
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.

1.58
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

1.27
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.86

Water Solubility

Log S (ESOL):?

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

-2.12
Solubility 1.97 mg/ml ; 0.00764 mol/l
Class?

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

Soluble
Log S (Ali)?

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

-2.73
Solubility 0.48 mg/ml ; 0.00187 mol/l
Class?

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

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

-1.46
Solubility 8.9 mg/ml ; 0.0346 mol/l
Class?

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

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

Yes
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

No
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

No
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

No
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.

-6.66 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<0.0
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)

2.26

Application In Synthesis of [ 154775-43-6 ]

* 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 [ 154775-43-6 ]

[ 154775-43-6 ] Synthesis Path-Downstream   1~32

  • 1
  • [ 1822-32-8 ]
  • [ 24424-99-5 ]
  • [ 154775-43-6 ]
YieldReaction ConditionsOperation in experiment
79% Step B. 1-tert-Butoxycarbonyl-4-piperidinepropionic acid 4-Piperidinepropionic acid (13.4mmoles) (prepared as described in Step A above), di-tert-butyldicarbonate (3.22g, 14.75mmoles) and sodium hydroxide (0.5364g, 13.4mmoles) are dissolved in THF-water (1:1) (40ml) and the mixture is stirred at 25C for 18h. The mixture is passed over Bio Rad 50WX4 (H+) resin (15ml bed) and the resin is washed with THF-water. The combined eluates are evaporated to dryness and then azeotroped with THF to give the title compound (2.72g, 79%), FABMS: m/z 258.1 (MH+).
  • 2
  • (R)-3-((S)-1-Ethoxycarbonylmethyl-4,4-dimethyl-pent-2-ynylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • [ 154775-43-6 ]
  • 4-{3-[(R)-3-((S)-1-Ethoxycarbonylmethyl-4,4-dimethyl-pent-2-ynylcarbamoyl)-piperidin-1-yl]-3-oxo-propyl}-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • 3
  • (R)-3-((S)-2-Ethoxycarbonyl-1-thiophen-2-yl-ethylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • [ 154775-43-6 ]
  • 4-{3-[(R)-3-((S)-2-Ethoxycarbonyl-1-thiophen-2-yl-ethylcarbamoyl)-piperidin-1-yl]-3-oxo-propyl}-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • 4
  • (R)-3-((S)-1-Ethoxycarbonylmethyl-3-phenyl-prop-2-ynylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • [ 154775-43-6 ]
  • 4-{3-[(R)-3-((S)-1-Ethoxycarbonylmethyl-3-phenyl-prop-2-ynylcarbamoyl)-piperidin-1-yl]-3-oxo-propyl}-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • 5
  • [ 184965-15-9 ]
  • [ 154775-43-6 ]
  • [ 184965-16-0 ]
  • 6
  • (R)-3-((S)-2-Ethoxycarbonyl-1-quinolin-3-yl-ethylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • [ 154775-43-6 ]
  • 4-{3-[(R)-3-((S)-2-Ethoxycarbonyl-1-quinolin-3-yl-ethylcarbamoyl)-piperidin-1-yl]-3-oxo-propyl}-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • 7
  • di-tert-butyl 2,2'-[[4-(aminoacetyl)-1,2-phenylene]bis(oxy)]diacetate hydrochloride [ No CAS ]
  • [ 154775-43-6 ]
  • [[4-[[N-[3-(piperidin-4-yl)propionyl]amino]acetyl]-o-phenylene]dioxy]diacetic acid [ No CAS ]
  • 8
  • [ 68641-49-6 ]
  • [ 154775-43-6 ]
  • C19H30N3O9P [ No CAS ]
  • 9
  • [ 162504-75-8 ]
  • [ 154775-43-6 ]
YieldReaction ConditionsOperation in experiment
A solution of tert-butyl 4- (3-METHOXY-3-OXOPROPYL) PIPERIDINE-1-CARBOXYLATE (2.0 g, 7.37 mmol) in 8 ml of methanol was added a solution of LIOH monohydrate (0.46g, 11.0 mmol) in 2 ml of water. The resulting solution was stirred at rt for 16h and it was concentrated under vacuum. To the residue was added 0.35 ml of acetic acid and 0.1 ml of water. The mixture was poured into a solution of EtOAc and CH2CL2 (1 : 1). The organic layer was dried with NA2SO4, filtered through celite and concentrated. To give 1.6g of 3- [1- (tert-butoxycarbonyl) piperidin-4- yl] propanoic acid.
  • 10
  • [ 90719-32-7 ]
  • [ 154775-43-6 ]
  • [ 195877-48-6 ]
  • 11
  • [ 154775-43-6 ]
  • [ 252990-05-9 ]
  • 4-[3-(1-<i>tert</i>-butoxycarbonyl-piperidin-4-yl)-propionyl]-piperazine-1,2-dicarboxylic acid 1-<i>tert</i>-butyl ester 2-methyl ester [ No CAS ]
  • 12
  • [ 154775-43-6 ]
  • [ 1027301-49-0 ]
  • 4-{3-[(R)-3-((S)-2-Methoxycarbonyl-1-thiophen-2-yl-ethylcarbamoyl)-piperidin-1-yl]-3-oxo-propyl}-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • 13
  • [ 154775-43-6 ]
  • [ 252989-40-5 ]
  • [ 223697-40-3 ]
  • 14
  • [ 154775-43-6 ]
  • [ 1027378-55-7 ]
  • 4-{3-[(R)-3-((R)-1-Methoxycarbonylmethyl-4,4-dimethyl-pent-2-ynylcarbamoyl)-piperidin-1-yl]-3-oxo-propyl}-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • 15
  • [ 154775-43-6 ]
  • (S)-6,6-Dimethyl-3-[((R)-piperidine-3-carbonyl)-amino]-hept-4-ynoic acid methyl ester [ No CAS ]
  • 4-{3-[(R)-3-((S)-1-Methoxycarbonylmethyl-4,4-dimethyl-pent-2-ynylcarbamoyl)-piperidin-1-yl]-3-oxo-propyl}-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • 16
  • [ 154775-43-6 ]
  • (S)-3-(6-Methyl-pyridin-3-yl)-3-[((R)-piperidine-3-carbonyl)-amino]-propionic acid methyl ester [ No CAS ]
  • 4-(3-{(R)-3-[(S)-2-Methoxycarbonyl-1-(6-methyl-pyridin-3-yl)-ethylcarbamoyl]-piperidin-1-yl}-3-oxo-propyl)-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • 17
  • [ 154775-43-6 ]
  • [ 1026529-52-1 ]
  • 4-(3-{(R)-3-[(S)-1-(5-Bromo-pyridin-3-yl)-2-methoxycarbonyl-ethylcarbamoyl]-piperidin-1-yl}-3-oxo-propyl)-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • 18
  • [ 154775-43-6 ]
  • [ 1026654-54-5 ]
  • 4-(3-{(R)-3-[(S)-1-(6-Chloro-pyridin-3-yl)-2-methoxycarbonyl-ethylcarbamoyl]-piperidin-1-yl}-3-oxo-propyl)-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • 19
  • [ 154775-43-6 ]
  • [ 1026290-16-3 ]
  • 4-{3-[(R)-3-((S)-1-Methoxycarbonylmethyl-3-phenyl-prop-2-ynylcarbamoyl)-piperidin-1-yl]-3-oxo-propyl}-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • 20
  • [ 154775-43-6 ]
  • (R)-5-Phenyl-3-[((R)-piperidine-3-carbonyl)-amino]-pent-4-ynoic acid methyl ester [ No CAS ]
  • 4-{3-[(R)-3-((R)-1-Methoxycarbonylmethyl-3-phenyl-prop-2-ynylcarbamoyl)-piperidin-1-yl]-3-oxo-propyl}-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • 21
  • [ 154775-43-6 ]
  • (S)-3-(5-Ethynyl-pyridin-3-yl)-3-[((R)-piperidine-3-carbonyl)-amino]-propionic acid methyl ester [ No CAS ]
  • 4-(3-{(R)-3-[(S)-1-(5-Ethynyl-pyridin-3-yl)-2-methoxycarbonyl-ethylcarbamoyl]-piperidin-1-yl}-3-oxo-propyl)-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • 22
  • [ 154775-43-6 ]
  • (S)-3-[((R)-Piperidine-3-carbonyl)-amino]-3-quinolin-3-yl-propionic acid methyl ester [ No CAS ]
  • 4-{3-[(R)-3-((S)-2-Methoxycarbonyl-1-quinolin-3-yl-ethylcarbamoyl)-piperidin-1-yl]-3-oxo-propyl}-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • 23
  • [ 154775-43-6 ]
  • (S)-3-[((S)-Piperidine-3-carbonyl)-amino]-3-quinolin-3-yl-propionic acid methyl ester [ No CAS ]
  • 4-{3-[(S)-3-((S)-2-Methoxycarbonyl-1-quinolin-3-yl-ethylcarbamoyl)-piperidin-1-yl]-3-oxo-propyl}-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • 24
  • [ 154775-43-6 ]
  • [ 1026422-28-5 ]
  • 4-(3-{(R)-3-[(S)-1-(5,6-Dichloro-pyridin-3-yl)-2-methoxycarbonyl-ethylcarbamoyl]-piperidin-1-yl}-3-oxo-propyl)-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • 25
  • [ 154775-43-6 ]
  • [ 1026597-57-8 ]
  • 4-(3-{(R)-3-[(S)-1-(5-Chloro-6-methoxy-pyridin-3-yl)-2-methoxycarbonyl-ethylcarbamoyl]-piperidin-1-yl}-3-oxo-propyl)-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • 26
  • [ 154775-43-6 ]
  • (S)-3-[((R)-Piperidine-3-carbonyl)-amino]-3-(6-thiophen-3-yl-pyridin-3-yl)-propionic acid methyl ester [ No CAS ]
  • 4-(3-{(R)-3-[(S)-2-Methoxycarbonyl-1-(6-thiophen-3-yl-pyridin-3-yl)-ethylcarbamoyl]-piperidin-1-yl}-3-oxo-propyl)-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • 27
  • [ 154775-43-6 ]
  • (2S,3R)-2-Hydroxy-4-phenyl-3-[((R)-piperidine-3-carbonyl)-amino]-butyric acid tert-butyl ester [ No CAS ]
  • 4-{3-[3-(1-benzyl-2-<i>tert</i>-butoxycarbonyl-2-hydroxy-ethylcarbamoyl)-piperidin-1-yl]-3-oxo-propyl}-piperidine-1-carboxylic acid <i>tert</i>-butyl ester [ No CAS ]
  • 28
  • [ 154775-43-6 ]
  • (S)-3-(5-Phenyl-pyridin-3-yl)-3-[((R)-piperidine-3-carbonyl)-amino]-propionic acid methyl ester [ No CAS ]
  • 4-(3-{(R)-3-[(S)-2-Methoxycarbonyl-1-(5-phenyl-pyridin-3-yl)-ethylcarbamoyl]-piperidin-1-yl}-3-oxo-propyl)-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • 29
  • [ 154775-43-6 ]
  • (S)-3-(3-Chloro-5-trifluoromethyl-pyridin-2-yl)-3-[((R)-piperidine-3-carbonyl)-amino]-propionic acid methyl ester [ No CAS ]
  • 4-(3-{(R)-3-[(S)-1-(3-Chloro-5-trifluoromethyl-pyridin-2-yl)-2-methoxycarbonyl-ethylcarbamoyl]-piperidin-1-yl}-3-oxo-propyl)-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • 30
  • [ 154775-43-6 ]
  • (S)-3-(5-Phenylethynyl-pyridin-3-yl)-3-[((R)-piperidine-3-carbonyl)-amino]-propionic acid methyl ester [ No CAS ]
  • 4-(3-{(R)-3-[(S)-2-Methoxycarbonyl-1-(5-phenylethynyl-pyridin-3-yl)-ethylcarbamoyl]-piperidin-1-yl}-3-oxo-propyl)-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • 31
  • [ 154775-43-6 ]
  • [ 1026337-11-0 ]
  • 4-(3-{(R)-3-[(S)-2-Methoxycarbonyl-1-(5-phenethyl-pyridin-3-yl)-ethylcarbamoyl]-piperidin-1-yl}-3-oxo-propyl)-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
  • 32
  • [ 154775-43-6 ]
  • dimethyl isoindolin-5,6-dicarboxylate [ No CAS ]
  • [ 262419-13-6 ]
 

Historical Records

Technical Information

Categories

Related Functional Groups of
[ 154775-43-6 ]

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Carboxylic Acids

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Related Parent Nucleus of
[ 154775-43-6 ]

Piperidines

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