154775-43-6|3-(1-(tert-Butoxycarbonyl)piperidin-4-yl)propanoic acid| Ambeed

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.

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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 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.61
Log P_o/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 P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.12
Log P_o/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 P_o/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 P_o/w? Consensus Log P_o/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 1~55

1
[ 1822-32-8 ]
[ 24424-99-5 ]
[ 154775-43-6 ]

Yield	Reaction Conditions	Operation 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+).

References: [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1227 - 1232.
[2]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 1151 - 1175.
[3]Organic and Biomolecular Chemistry,2012,vol. 10,p. 6169 - 6185.
[4]Patent: EP931078,2006,B1 .Location in patent: Page/Page column 72.
[5]Organic and Biomolecular Chemistry,2016,vol. 14,p. 2318 - 2326.
[6]Bioorganic and Medicinal Chemistry Letters,1996,vol. 6,p. 2601 - 2606.
[7]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1629 - 1633.

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 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1996,vol. 6,p. 2371 - 2376.

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 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1996,vol. 6,p. 2371 - 2376.

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 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1996,vol. 6,p. 2371 - 2376.

5
[ 184965-15-9 ]
[ 154775-43-6 ]
[ 184965-16-0 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1996,vol. 6,p. 2371 - 2376.

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 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1996,vol. 6,p. 2371 - 2376.

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 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1996,vol. 6,p. 2601 - 2606.

8
[ 68641-49-6 ]
[ 154775-43-6 ]
C₁₉H₃₀N₃O₉P [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 2492 - 2502.

9
[ 162504-75-8 ]
[ 154775-43-6 ]

Yield	Reaction Conditions	Operation 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.

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 2492 - 2502.
[2]Patent: WO2004/58702,2004,A2 .Location in patent: Page 36-37; 21.

10
[ 90719-32-7 ]
[ 154775-43-6 ]
[ 195877-48-6 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1227 - 1232.

11
[ 154775-43-6 ]
[ 252990-05-9 ]
4-[3-(1-tert-butoxycarbonyl-piperidin-4-yl)-propionyl]-piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester [ No CAS ]