Naphtho[2,1-b][1,5] and [1,2-f][1,4]oxazocines as selective NK1 antagonists.
Previously we reported on the synthesis and properties of a series of highly potent piperidinyl 2-subsituted-3-cyano-1-naphthamide NK1 antagonists that includes 3 and 4. Here we report our efforts to alleviate a troublesome atropisomeric property of those derivatives by introduction of a tethering bridge that, in addition, could be used to lock the resulting cyclic derivatives in a purported NK1 pharmacophore conformation. Using 3 as a starting point, the naphtho[2,1-b][1,5]oxazocine, 17, was found to contain the optimal ring tether size (8) for retaining NK1 activity, was more NK1 versus NK2 selective, and reduced the number of atropisomers from four to two. Cyclic derivatives 29 and 32, which exist as essentially single atropisomers in the purported pharmacophore conformation, were prepared in the closely related naphtho[1,2-f][1,4]oxazocine series as part of an effort to use mono methyl substitution of the tethering bridge as a conformation stabilizing factor. Both 29 and 32 were found to be less active as NK1 antagonists than the non-methylated parent 28 possibly due to methyl group destabilization of receptor interaction. We discuss the above findings in the context of a previously proposed NK1 pharmacophore model and present a further refinement of that model.
Ohnmacht
Cyrus J
CJ
Department of Medicinal Chemistry, AstraZeneca Pharmaceuticals LP, PO Box 15437, Wilmington, DE 19850-5437, USA. cyrus.ohnmacht@astrazeneca.com
Albert
Jeffrey S
JS
Bernstein
Peter R
PR
Rumsey
William L
WL
Masek
Brian B
BB
Dembofsky
Bruce T
BT
Koether
Gerard M
GM
Andisik
Donald W
DW
Aharony
David
D
D000818:Animals; D002460:Cell Line; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008968:Molecular Conformation; D015394:Molecular Structure; D064729:Neurokinin-1 Receptor Antagonists; D010079:Oxazocines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D064729:Neurokinin-1 Receptor Antagonists; D010079:Oxazocines