356057-34-6

Basic information

• Product Name: DARAPLADIB
• Synonyms: N-[2-(Diethylamino)ethyl]-N-[4'-(trifluoromethyl)-1,1'-biphenyl-4-ylmethyl]-2-[2-(4-fluorobenzylthio)-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl]acetamide;SB 435445;SB 480848;Darapladib API;Darapladib(SB-480848);N-[2-(diethylamino)ethyl]-2-[[(4-fluorophenyl)methyl]thio]-4,5,6,7-tetrahydro-4-oxo-N-[[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl]-1H-Cyclopentapyrimidine-1-acetamide;N-(2-(Diethylamino)ethyl)-2-(2-((4-fluorobenzyl)thio)-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)-N-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)acetamide;N-[2-(Diethylamino)ethyl]-N-[4'-(trifluoromethyl)-1,1'-biphenyl-4-ylmethyl]-2-[2-(4-fluorobenz
• CAS NO: 356057-34-6
• Molecular Formula: C36H38F4N4O2S
• Molecular Weight: 666.79
• Product Categories: Inhibitors
• Mol File: 356057-34-6.mol

Chemical Properties

• Boiling Point: 741.002 °C at 760 mmHg
• Flash Point: 401.944 °C
• Appearance: /
• Density: 1.25
• Storage Temp.: Inert atmosphere,Store in freezer, under -20°C
• Solubility: ≥32.95 mg/mL in DMSO; insoluble in H2O; ≥891 mg/mL in EtOH
• PKA: 9.03±0.10(Predicted)
• CAS DataBase Reference: DARAPLADIB(CAS DataBase Reference)
• NIST Chemistry Reference: DARAPLADIB(356057-34-6)
• EPA Substance Registry System: DARAPLADIB(356057-34-6)

Safety Data

• Hazardous Substances Data: 356057-34-6(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Darapladib is used as a therapeutic agent for the treatment of atherosclerosis. As an Lp-PLA2 inhibitor, it helps in managing the inflammation and oxidative stress associated with atherosclerotic plaques, thereby reducing the risk of cardiovascular events.

In vitro

During the copper catalysed oxidation of human LDL, Darapladib prevents the production of lyso-PtdCho with IC50 of 4 nM and subsequent monocyte chemotaxis with IC50 of 4 nM.

In vivo

In the WHHL rabbits, Darapladib (30 mg/kg p.o.) exhibits excellent inhibition of Lp-PLA2 within the atherosclerotic plaque by 95%. Darapladib, as an inhibitor of Lp-PLA2, reduces development of advanced coronary atherosclerosis in diabetic and hypercholesterolemic (DMHC) pigs. In DMHC pigs, darapladib reduces the amount of IgG-immunopositive material that leaked into the brain and also the density of Aβ42-containing neurons.

Biological Activity

plaque rupture is responsible for the clinical events of ischemic death, myocardial infarction, acute coronary syndromes and ischemic strokes. lipoprotein-associated phospholipase a2 (lp-pla2) seems to play a major role in the development of such high-risk lesions, in both the coronary and carotid arteries. darapladib is a selective inhibitor of lp-pla2.

in vitro

darapladib potently inhibited lp-pla2 with an ic50 of 270 pm. a lack of selectivity against other secretory pla2s postulated to play a role in atherogenesis had been demonstrated. the percentage inhibition achieved when 1 μm darapladib was evaluated against human secretory pla2s iia, v and x, was 0, 0 and 8.7%, respectively [1].

in vivo

inhibition of lp-pla2 by darapladib led to attenuation of inflammation in vivo and decreased plaque formation in apoe-deficient mice, suggesting an anti-atherogenic role during the progression of atherosclerosis [2].

references

[1] bui qt, wilensky rl. darapladib. expert opin investig drugs. 2010;19(1):161-8. [2] wang wy, zhang j, wu wy, li j, ma yl, chen wh, yan h, wang k, xu ww, shen jh, wang yp. inhibition of lipoprotein-associated phospholipase a2 ameliorates inflammation and decreases atherosclerotic plaque formation in apoe-deficient mice. plos one. 2011;6(8):e23425. [3] mohler er 3rd, ballantyne cm, davidson mh, hanefeld m, ruilope lm, johnson jl, zalewski a; darapladib investigators. the effect of darapladib on plasma lipoprotein-associated phospholipase a2 activity and cardiovascular biomarkers in patients with stable coronary heart disease or coronary heart disease risk equivalent: the results of a multicenter, randomized, double-blind, placebo-controlled study. j am coll cardiol. 2008;51(17):1632-41.

Upstream product

• 128796-39-4 4-trifluoromethylphenylboronic acid 
• 1122-91-4 4-bromo-benzaldehyde 
• 90035-34-0 4-(4-trifluoromethylphenyl)benzaldehyde 
• 451487-18-6 2-[(4-fluorobenzyl)sulfanyl]-1,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one 
• 35563-27-0 2-mercapto-1,5,6,7-tetrahydro-cyclopentapyrimidin-4-one 
• 611-10-9 2-ethoxycarbonyl-1-cyclopentanone 
• 304694-40-4 N,N-diethyl-N'-(4'-trifluoromethylbiphenyl-4-ylmethyl)ethane-1,2-diamine 
• 356058-42-9 {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl}acetic acid 
• 1349902-20-0 2-(4-oxo-2-thioxo-2,3,4,5,6,7-hexahydro-1H-cyclopenta-[d]-pyrimidin-1-yl) acetic acid 
• 1349902-19-7 sodium ({2-[(methyloxy)carbonyl]-1-cyclopenten-1-yl}amino)acetate 
• 1349902-21-1 C₁₉H₁₇FN₄O₂S 
• 10472-24-9 methyl 2-oxocyclopentane-1-carboxylate 
• 100-36-7 N,N-diethylethylenediamine 

Relevant articles and documents

RADIOLABELED DARAPLADIB AND ANALOGS THEREOF AND THEIR USE AS IMAGING COMPOUNDS

The present inventors have developed new radiolabeled Darapladib and analogs thereof which can be used for the specific detection of vulnerable atherosclerotic plaques by targeting lipoprotein-associated phospholipase A2 (Lp-PLA2) which is a biomarker of

Regioselectivity of thiouracil alkylation: Application to optimization of Darapladib synthesis

Darapladib is one of the most potent Lp-PLA2 (Lipoprotein-associated phospholipase A2) inhibitor with an IC50 of 0.25 nM. We demonstrate that a crucial step of Darapladib synthesis was not correctly described in the litera

PROCESSES FOR THE PREPARATION OF DARAPLADIB AND ITS INTERMEDIATES

The present invention provides a process for the preparation of ethyl {2-[(4- fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl}acetate of Formula 4, {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta [d]pyri

Selective inhibitors and tailored activity probes for lipoprotein- associated phospholipase A2

Lipoprotein-associated phospholipase A2 (Lp-PLA2 or PLA2G7) binds to low-density lipoprotein (LDL) particles, where it is thought to hydrolyze oxidatively truncated phospholipids. Lp-PLA2 has also been implicate

NOVEL PROCESSES

This invention relates to methods of making a compound of formula (I) and intermediates for same. The compounds of formula (I) being useful for treating cardiovascular and inflammatory diseases such as atherosclerosis.

METHODS OF TREATMENT AND PREVENTION OF NEURODEGENERATIVE DISEASES AND DISORDERS

The present invention provides compostions and methods useful for treating and preventing neurodegenerative disease and neurologically related disorders by inhibition of Lp-PLA2. The compositions and methods are useful for treating and preventing diseases

METHODS OF TREATMENT AND PREVENTION OF METABOLIC BONE DISEASES AND DISORDERS

The present invention provides compostions and methods useful for treating and preventing metabolic bone diseases and disorders by inhibition of Lp-PLA2. The compositions and methods are useful for treating and preventing metabolic bone disease

The identification of clinical candidate SB-480848: A potent inhibitor of lipoprotein-associated phospholipase A2

Modification of the pyrimidone 5-substituent in clinical candidate SB-435495 has given a series of inhibitors of recombinant lipoprotein-associated phospholipase A2 with sub-nanomolar potency. Cyclopentyl fused derivative 21, SB-480848, showed an enhanced in vitro and in vivo profile versus SB-435495 and has been selected for progression to man.

Novel compounds

Pyrimidone compounds of formula (I): are inhibitors of the enzyme Lp-PLA2 and are of use in treating atheroscelerosis.