Synthesis and pharmacological characterization of 5-phenyl-2-[2-(1- piperidinylcarbonyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-1-ones: A new class of Neuropeptide S antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 24, 2010, Pages 7308-7311

  Micheli, Fabrizio ^a   Di Fabio, Romano ^a   Giacometti, Angelo ^a   Roth, Adelheid ^a   Moro, Elisa ^a   Merlo, Giancarlo ^a   Paio, Alfredo ^a   Merlo Pich, Emilio ^a   Tomelleri, Silvia ^a   Tonelli, Federica ^a   Zarantonello, Paola ^a   Zonzini, Laura ^a   Capelli, Anna Maria ^a  

^a GSK   (Italy)

Author keywords

Antagonist; GPR154; Neuropeptide S; NPS

Indexed keywords

5 PHENYL 2 [2 (1 PIPERIDINYLCARBONYL)PHENYL] 2,3 DIHYDRO 1H PYRROLO[1,2 C]IMIDAZOL 1 ONE DERIVATIVE; IMIDAZOLE DERIVATIVE; NEUROPEPTIDE S; UNCLASSIFIED DRUG;

ARTICLE; DRUG ACTIVITY; DRUG SCREENING; DRUG SYNTHESIS; NUCLEAR MAGNETIC RESONANCE;

ANIMALS; AZABICYCLO COMPOUNDS; COMPUTER SIMULATION; DRUG DESIGN; HUMANS; IMIDAZOLES; MICROSOMES, LIVER; NEUROPEPTIDES; PIPERIDINES; RATS; THERMODYNAMICS;

EID: 78449290066     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.10.067     Document Type: Article

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20. Conformational analyses were carried out with BatchMin V9.5 and V9.6 (Schrodinger, http://www.schrodinger.com ). Conformational sampling was done with Low-frequency-Mode Conformational Search (LMCS keyword), OPLS-2005 force field, implicit water model. 1000 Monte Carlo steps per rotatable bond, 10,000 minimization steps and 50 kJ/mol energy window were set. A root mean square deviation cutoff of 0.5 was utilized to discard duplicated conformations. Conformations were visually inspected within Maestro (Schrodinger). Atom-based superimpositions were performed with the use of the routines available within Maestro.
21. f) of each conformation j was calculated as the ratio between p(j)/totp where p(j) = exp(-1((energy(j) - energy(lowest)/(RT))) and totp = sum(p(j)) over all the conformations sampled within 50 kJ/mol energy window, energy(j) is the energy of the conformation j, energy(lowest) is the energy of the lowest energy conformation, R = 8.31434/1000 and T = 300 K.
22. 4 and dimethylethane diamine to give the desired product.
23. 2 in MeOH. The resulting amino derivative was cyclized with EtONa and EtOH to give 6-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one. This intermediate was coupled with 1-[(2-bromophenyl)carbonyl]piperidine as described in Ref. 14 to give the title material.
24. 2 blanket. NaH was added and the mixture stirred for 0.3 h; iodochlorometane was added drop-wise and the reaction was stirred for 24 h at 60 °C to give, after quenching and work-up, the title compound.
25. All the works involving animals were carried out in accordance with European directive 86/609/EEC governing animal welfare and protection, which is acknowledged by Italian Legislative Decree no. 116, 27 January 1992, and according to internal review performed by the GlaxoSmithKline Committee on Animal Research & Ethics (CARE) and to the company Policy on the Care and Use of Laboratory Animals.