3-Oxo-2-piperazinyl acetamides as potent bradykinin B1 receptor antagonists for the treatment of pain and inflammation

The discovery of novel and highly potent oxopiperazine based B1 receptor antagonists is described. Compared to the previously described arylsulfonylated ( R)-3-amino-3-phenylpropionic acid series, the current compounds showed improved in vitro potency and metabolic stability. Compound 17, 2-((2 R)-1...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2011-06, Vol.21 (11), p.3384-3389
Hauptverfasser:	Chen, Jian Jeffrey, Nguyen, Thomas, D’Amico, Derin C., Qian, Wenyuan, Human, Jason, Aya, Toshihiro, Biswas, Kaustav, Fotsch, Christopher, Han, Nianhe, Liu, Qingyian, Nishimura, Nobuko, Peterkin, Tanya A.N., Yang, Kevin, Zhu, Jiawang, Riahi, Babak Bobby, Hungate, Randall W., Andersen, Neil G., Colyer, John T., Faul, Margaret M., Kamassah, Augustus, Wang, Judy, Jona, Janan, Kumar, Gondi, Johnson, Eileen, Askew, Benny C.
Format:	Artikel
Sprache:	eng
Schlagworte:	acetamides Acetamides - chemical synthesis Acetamides - chemistry Acetamides - therapeutic use acetic acids Analgesics Animals Antagonist antagonists Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents bradykinin Bradykinin B1 Bradykinin B1 Receptor Antagonists chemistry Dogs GPCR Inflammation Inflammation - drug therapy Inhibitory Concentration 50 Medical sciences Mice Models, Animal Molecular Structure Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Oxopiperazine Pain Pain - drug therapy Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems Pharmacology. Drug treatments Piperazines - chemical synthesis Piperazines - chemistry Piperazines - therapeutic use Rabbits Rats Receptor, Bradykinin B1 - chemistry Stereoisomerism Structure-Activity Relationship Tetralin
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Beschreibung
Zusammenfassung:	The discovery of novel and highly potent oxopiperazine based B1 receptor antagonists is described. Compared to the previously described arylsulfonylated ( R)-3-amino-3-phenylpropionic acid series, the current compounds showed improved in vitro potency and metabolic stability. Compound 17, 2-((2 R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)- N-((1 R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide, showed EC 50 of 10.3 nM in a rabbit biochemical challenge model. The practical syntheses of chiral arylsulfonylated oxopiperazine acetic acids are also described.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2011.03.115