The discovery of potent, selective, and orally bioavailable hNK1 antagonists derived from pyrrolidine

SAR studies on amides, ureas, and vinylogous amides derived from pyrrolidine led to the discovery of several potent hNK(1) antagonists. One particular vinylogous amide (45b) had excellent potency, selectivity, pharmacokinetic profile, and functional activity in vivo. An in vivo rhesus macaque brain...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2007-09, Vol.17 (18), p.5191-5198
Hauptverfasser:	LIN, Peter, LEHUA CHANG, KURTZ, Marc M, TSAO, Kwei-Lan C, WHEELDON, Alan, CARLSON, Emma J, ENG, Waisi, BURNS, H. Donald, HARGREAVES, Richard J, MILLS, Sander G, DEVITA, Robert J, YOUNG, Jonathan R, EID, Ronsar, XINCHUN TONG, SONG ZHENG, BALL, Richard G, TSOU, Nancy N, CHICCHI, Gary G
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Animals Biological and medical sciences Biological Availability Brain - metabolism Humans Macaca mulatta Medical sciences Neurokinin-1 Receptor Antagonists Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems Pharmacology. Drug treatments Pyrrolidines - pharmacokinetics Pyrrolidines - pharmacology Species Specificity
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Zusammenfassung:	SAR studies on amides, ureas, and vinylogous amides derived from pyrrolidine led to the discovery of several potent hNK(1) antagonists. One particular vinylogous amide (45b) had excellent potency, selectivity, pharmacokinetic profile, and functional activity in vivo. An in vivo rhesus macaque brain receptor occupancy PET study for compound 45b revealed an estimated Occ(90) approximately 300 ng/ml.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2007.06.085