Short and efficient syntheses of analogues of WAY-100635: new and potent 5-HT1A receptor antagonists.
Simple syntheses of four new and potent analogues of the 5-HT1A receptor ligand, WAY-100635 are described, namely the 6-(pyridinyl)-bromo-, the 6-(pyridinyl)-fluoro-, the pyrimidine- and the 5-(pyridinyl)-bromo-analogues. The first three analogues were obtained by aromatic nucleophilic substitution of the 2,6-dihalogenopyridine (activated or not as an N-oxide) or of the 2-chloropyrimidine with the corresponding amine nucleophile as a key step. The fourth analogue, the 5-(pyridinyl)-bromo-analogue, was synthesized from the 2-amino-5-bromopyridine via a progressive elongation of the skeleton. The four compounds described are all full antagonists and show good in vitro binding affinities (Ki).
Marchais
S
S
Department of Medicinal Chemistry, University Center for Pharmacy, University of Groningen, The Netherlands. marchais@farm.rug.nl
Nowicki
B
B
Wikström
H
H
Brennum
L T
LT
Halldin
C
C
Pike
V W
VW
D000242:Cyclic AMP / Q000096:biosynthesis; D005462:Fluorine Radioisotopes; D006801:Humans; D050356:Lipid Metabolism; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D005462:Fluorine Radioisotopes; D010879:Piperazines; D011725:Pyridines; D019275:Radiopharmaceuticals; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D000242:Cyclic AMP