Synthesis and biological evaluation of NK1 antagonists derived from L-tryptophan.
The 3,5-bis(trifluoromethyl)benzyl ester of N-acetyl-L-tryptophan (3), which was derived from the screening lead N-ethyl-L-tryptophan benzyl ester, has been used as a starting point to identify high-affinity substance P receptor antagonists with improved in vivo activity. Altering the ester moiety to an amide or ether led to a substantial loss in binding affinity, but conversion to a ketone provided compounds with affinity comparable to the equivalent esters. A homochiral synthesis of the key intermediate amino ketone 15 was developed which allows its preparation on a large scale. From this intermediate a range of amine-containing acylamino derivatives were prepared with affinity optimized in the morpholinylbutyramide 161 which has an IC50 of 0.17 nM at the human NK1 receptor. In addition to improving affinity, the amino group also provided aqueous solubility for a number of these derivatives. When tested in vivo the quinuclidine derivative L-737,488 (16i) was found to be an orally active (ID50 = 1.8 mg/kg) inhibitor of substance P-induced dermal extravasation in the guinea pig.
MacLeod
A M
AM
Merck, Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, U.K.
Cascieri
M A
MA
Merchant
K J
KJ
Sadowski
S
S
Hardwicke
S
S
Lewis
R T
RT
MacIntyre
D E
DE
Metzger
J M
JM
Fong
T M
TM
Shepheard
S
S
D000588:Amines / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D016466:CHO Cells; D002319:Cardiovascular System / Q000187:drug effects; D006224:Cricetinae; D004952:Esters / Q000138:chemical synthesis / Q000494:pharmacology; D005119:Extravasation of Diagnostic and Therapeutic Materials / Q000188:drug therapy; D005260:Female; D005289:Ferrets; D006168:Guinea Pigs; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008969:Molecular Sequence Data; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship; D013373:Substance P / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014364:Tryptophan / Q000031:analogs & derivatives*
D000588:Amines; D001713:Biphenyl Compounds; D004952:Esters; D006571:Heterocyclic Compounds; D006993:Hypnotics and Sedatives; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D013373:Substance P; D014364:Tryptophan; C066892:CP 96345