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Chemical Structure| 52409-22-0 Chemical Structure| 52409-22-0

Structure of 52409-22-0

Chemical Structure| 52409-22-0

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Evan S. O& ; amp ; amp ; #39 ; Brien ; Vipin Ashok Rangari , et al.

Abstract: The µ-opioid receptor (µOR) is a well-established target for analgesia1, yet conventional agonists cause serious adverse efects, notably addiction and respiratory depression. These factors have contributed to the current opioid overdose epidemic driven by fentanyl2, a highly potent synthetic opioid. µOR negative allosteric modulators (NAMs) may serve as useful tools in preventing opioid overdose deaths, but promising chemical scafolds remain elusive. Here we screened a large DNA-encoded chemical library against inactive µOR, counter-screening with active, G-protein and agonist-bound receptor to ‘steer’ hits towards conformationally selective modulators. We discovered a NAM compound with high and selective enrichment to inactive µOR that enhances the afnity of the key opioid overdose reversal molecule, naloxone. The NAM works cooperatively with naloxone to potently block opioid agonist signalling. Using cryogenic electron microscopy, we demonstrate that the NAM accomplishes this efect by binding a site on the extracellular vestibule in direct contact with naloxone while stabilizing a distinct inactive conformation of the extracellular portions of the second and seventh transmembrane helices. The NAM alters orthosteric ligand kinetics in therapeutically desirable ways and works cooperatively with low doses of naloxone to efectively inhibit various morphine-induced and fentanyl-induced behavioural efects in vivo while minimizing withdrawal behaviours. Our results provide detailed structural insights into the mechanism of negative allosteric modulation of the µOR and demonstrate how this can be exploited in vivo.

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Lish, Matthew S ; McKeon, Jillian EM ; Palmentiero, Caroline M ; Pomeroy, Julia M ; Roster, Colm P ; Guzei, Ilia A , et al.

Abstract: Primary amoebic meningoencephalitis (PAM) is a human brain infection caused by Naegleria fowleri with a 97% mortality rate. Quinazolinones resulting from a Mannich-coupled domino rearrangement were recently identified as inhibitors of the amoeba. Herein, we resolved the effective concentrations for 25 pilot compounds and then, using the Mannich protocol and a key late-stage, N-demethylation/functionalization, we synthesized 53 additional analogs to improve potency, solubility and microsomal stability. We established an antiamoebic quinazolinone pharmacophore, culminating in (±)-trans-57b which featured the best combination of potency, selectivity index, solubility, and microsomal stability. Enantiomeric separation afforded (4aS,13bR)-57b (BDGR-20237) with a 41-fold potency advantage over its enantiomer. ADME and mouse pharmacokinetic profiling for BDGR-20237 revealed high brain penetrance but a limited half-life which did not statistically enhance the mouse survival in a pilot efficacy study. The pharmacophoric model, supported by 88 quinazolinones, several of which exhibit subnanomolar potency, will guide further scaffold optimization.

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Product Details of [ 52409-22-0 ]

CAS No. :52409-22-0
Formula : C51H42O3Pd2
M.W : 915.72
SMILES Code : O=C(/C=C/C1=CC=CC=C1)/C=C/C2=CC=CC=C2.O=C(/C=C/C3=CC=CC=C3)/C=C/C4=CC=CC=C4.O=C(/C=C/C5=CC=CC=C5)/C=C/C6=CC=CC=C6.[Pd].[Pd]
MDL No. :MFCD00013310

Safety of [ 52409-22-0 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H302-H350-H411
Precautionary Statements:P201-P202-P264-P270-P280-P301+P312-P308+P313-P330-P403-P501
Class:9
UN#:3077
Packing Group:

Application In Synthesis of [ 52409-22-0 ]

* 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 [ 52409-22-0 ]

[ 52409-22-0 ] Synthesis Path-Downstream   1~5

  • 1
  • [ 110-91-8 ]
  • [ 52409-22-0 ]
  • trifluoromethanesulfonic acid 4-acetyl-3,5-dihydroxy-phenyl ester [ No CAS ]
  • [ 224311-51-7 ]
  • [ 404011-08-1 ]
YieldReaction ConditionsOperation in experiment
475 mg (60%) With potassium phosphate; In tetrahydrofuran; EXAMPLE 144 1-(2,6-Dihydroxy-4-morpholin-4-yl-phenyl)-ethanone A solution of trifluoromethanesulfonic acid 4-acetyl-3,5-dihydroxy-phenyl ester (1.0 g, 3.33 mmol), morpholine (0.35 mL, 3.99 mmol), tris-(dibenzylideneacetone)dipalladium(0) (153 mg, 0.167 mmol), <strong>[224311-51-7]biphenyl-2-yl-di-tert-butyl-phosphane</strong> (198 mg, 0.666 mmol), and K3PO4 (1.41 mg, 6.66 mmol) in THF (2 mL) was heated to 85° C. in a sealed tube for 2 h. The reaction mixture was allowed to cool to room temperature, and filtered through a 3/4" silica gel (60 A) plug. The plug was washed with EtOAc (75 mL) and the filtrate concentrated. The concentrate was purified via Biotage chromatography with gradient elution from 100percent hexanes to 40percent EtOAc/hexanes to yield 475 mg (60percent) of 1-(2,6-dihydroxy-4-morpholin-4-yl-phenyl)-ethanone. Rf=0.16 (50percent EtOAc/hexanes). 1H NMR (CDCl3, 400 MHz) delta7.26 (s, 2H), 5.82 (s, 2H), 3.79 (c, 4H), 3.26 (m, 4H), 2.65 (s, 3H). LRMS (Electrospray, positive): Da/e 238.3 (m+1).
  • 2
  • [ 52409-22-0 ]
  • [ 22282-75-3 ]
  • [ 6163-58-2 ]
  • [ 203520-03-0 ]
  • [ 211820-04-1 ]
YieldReaction ConditionsOperation in experiment
In 1,4-dioxane; dichloromethane; To a suspension of <strong>[22282-75-3]3-fluoro-4-iodopyridine</strong> (2.23 g), 1-(tert-butoxycarbonyl)-4-(piperidin-4-ylcarbonyl)piperazine (1.49 g) and sodium t-butoxide (1.06 g) in 1,4-dioxan (20 ml) was added tris(dibenzylidene acetone)dipalladium(0) (0.09 g) and tri-o-tolylphosphine (0.12 g) and the mixture heated at reflux for 3 hours. The mixture was diluted with diethyl ether and washed with saturated aqueous sodium chloride solution, dried (Na2SO4) and evaporated. The residue was purified by chromatography on alumina (N32-63) eluding with 0.4percent methanol in dichloromethane to give as a solid, 1-(tert-butoxycarbonyl)-4-[1-(3-fluoro-4-pyridyl)piperidin-4-ylcarbonyl]piperazine (0.70 g). 1H-NMR (CDCl3): 1.45 (s, 9H), 1.80 (m, 2H), 2.00 (m, 2H), 2.65 (m, 1H), 2.90 (m, 2H), 3.40 (m, 8H), 3.80 (m, 2H), 6.70 (dd, 1H), 8.10 (d, 1H) and 8.20 (d, 1H); m/z 393 (M+1).
In 1,4-dioxane; dichloromethane; To a suspension of <strong>[22282-75-3]3-fluoro-4-iodopyridine</strong> (2.23 g), 1-(tert-butoxycarbonyl)-4-(piperidin-4-ylcarbonyl) piperazine (1.49 g) and sodium t-butoxide (1.06 g) in 1,4-dioxan (20 ml) was added tris(dibenzylidene acetone)dipalladium(0) (0.09 g) and tri-o-tolylphosphine (0.12 g) and the mixture heated at reflux for 3 hours. The mixture was diluted with diethyl ether and washed with saturated aqueous sodium chloride solution. dried (Na2SO4) and evaporated. The residue was purified by chromatography on alumina (N32-63) eluding with 0.4percent methanol in dichloromethane to give as a solid, 1-(tert-butoxycarbonyl)-4-[1-(3-fluoro-4-pyridyl)piperidin-4-ylcarbonyl]piperazine (0.70 g). 1H-NMR (CDCl3): 1.45 (s, 9H), 1.80 (m, 2H), 2.00 (m, 2H), 2.65 (m, 1H), 2.90 (m, 2H), 3.40 (m, 8H), 3.80 (m, 2H), 6.70 (dd, 1H), 8.10 (d, 1H) and 8.20 (d, 1H); m/z 393 (M+1).
  • 3
  • [ 52409-22-0 ]
  • [ 131274-22-1 ]
  • [ 53199-31-8 ]
  • 4
  • [ 52409-22-0 ]
  • [ 658-27-5 ]
  • C23H19FN2 [ No CAS ]
  • 5
  • 5-(di-tert-butylphosphino)-1′, 3′, 5′-triphenyl-1′H-[1,4′]bipyrazole [ No CAS ]
  • [ 52409-22-0 ]
  • [ 5744-80-9 ]
  • C37H42BrN6PPd [ No CAS ]
 

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