Structure-activity relationships in a series of NPY Y5 antagonists: 3-amido-9-ethylcarbazoles, core-modified analogues and amide isosteres.
Beginning with carbazole 1a, the amide and alkyl substituents were optimized to maintain potency while adding solubilizing groups. Efforts to replace the 3-amino-9-ethylcarbazole core, a known carcinogen, used the SAR generated in the carbazole series for guidance and led to the synthesis of a number of core-modified analogues. In addition, an isosteric series, in which the amide was replaced with an imidazole, was prepared. Two potent new series lacking the putative toxicophore were identified from these endeavors.
Hammond
Marlys
M
Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, CT 06340, USA. marlys_hammond@groton.pfizer.com
Elliott
Richard L
RL
Gillaspy
Melissa L
ML
Hager
David C
DC
Hank
Richard F
RF
LaFlamme
Janet A
JA
Oliver
Robert M
RM
DaSilva-Jardine
Paul A
PA
Stevenson
Ralph W
RW
Mack
Christine M
CM
Cassella
James V
JV
D000577:Amides / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000737:chemistry / Q000494:pharmacology; D002227:Carbazoles / Q000737:chemistry* / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D012995:Solubility; D013329:Structure-Activity Relationship
D000577:Amides; D002227:Carbazoles; D007093:Imidazoles; D017476:Receptors, Neuropeptide Y; C100568:neuropeptide Y5 receptor; C029899:imidazole; D002118:Calcium