Tryptophan-derived NK1 antagonists: conformationally constrained heterocyclic bioisosteres of the ester linkage.
The 3,5-bis(trifluoromethyl)benzyl ester of N-acetyl-L-tryptophan 1 (L-732,138) has been identified previously as a potent and selective substance P receptor antagonist. A series of analogs which introduced a 6-membered heterocyclic ring into the backbone of this structure were prepared for evaluation as bioisosteric replacements of the ester linkage of 1. The 2,5-dioxopiperazine 2 had very weak receptor affinity, but 2-oxopiperazine 5 exhibited modest activity. Examination of the conformations accessible to the substituents on these templates led to exploration of the corresponding 5-membered heterocyclic rings. This study culminated in the identification of oxazolidinedione 14 as a suitable ester mimic in terms of the retention of good NK1 binding affinity.
Lewis
R T
RT
Merck Sharp & Dohme Research Laboratories, Neuroscience Research Center, Harlow, Essex, U.K.
Macleod
A M
AM
Merchant
K J
KJ
Kelleher
F
F
Sanderson
I
I
Herbert
R H
RH
Cascieri
M A
MA
Sadowski
S
S
Ball
R G
RG
Hoogsteen
K
K
D000818:Animals; D016466:CHO Cells / Q000502:physiology; D006224:Cricetinae; D018360:Crystallography, X-Ray; D004952:Esters / Q000138:chemical synthesis / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008968:Molecular Conformation; D015394:Molecular Structure; D064729:Neurokinin-1 Receptor Antagonists; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D012996:Solutions; D013329:Structure-Activity Relationship; D014162:Transfection; D014364:Tryptophan / Q000031:analogs & derivatives*
D004952:Esters; D006571:Heterocyclic Compounds; D064729:Neurokinin-1 Receptor Antagonists; D010879:Piperazines; D018040:Receptors, Neurokinin-1; D012996:Solutions; D014364:Tryptophan