Fluorination of 3-(3-(piperidin-1-yl)propyl)indoles and 3-(3-(piperazin-1-yl)propyl)indoles gives selective human 5-HT1D receptor ligands with improved pharmacokinetic profiles.
It has previously been reported that a 3-(3-(piperazin-1-yl)propyl)indole series of 5-HT1D receptor ligands have pharmacokinetic advantages over the corresponding 3-(3-(piperidin-1-yl)propyl)indole series and that the reduced pKa of the piperazines compared to the piperidines may be one possible explanation for these differences. To investigate this proposal we have developed versatile synthetic strategies for the incorporation of fluorine into these ligands, producing novel series of 4-fluoropiperidines, 3-fluoro-4-aminopiperidines, and both piperazine and piperidine derivatives with one or two fluorines in the propyl linker. Ligands were identified which maintained high affinity and selectivity for the 5-HT1D receptor and showed agonist efficacy in vitro. The incorporation of fluorine was found to significantly reduce the pKa of the compounds, and this reduction of basicity was shown to have a dramatic, beneficial influence on oral absorption, although the effect on oral bioavailability could not always be accurately predicted.
van Niel
M B
MB
Department of Medicinal Chemistry, Merck, Sharp & Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, United Kingdom.
Collins
I
I
Beer
M S
MS
Broughton
H B
HB
Cheng
S K
SK
Goodacre
S C
SC
Heald
A
A
Locker
K L
KL
MacLeod
A M
AM
Morrison
D
D
Moyes
C R
CR
O'Connor
D
D
Pike
A
A
Rowley
M
M
Russell
M G
MG
Sohal
B
B
Stanton
J A
JA
Thomas
S
S
Verrier
H
H
Watt
A P
AP
Castro
J L
JL
D000284:Administration, Oral; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D017611:Fluorine Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000378:metabolism*; D013329:Structure-Activity Relationship
D017611:Fluorine Compounds; C470302:HTR1B protein, human; D007211:Indoles; D008024:Ligands; D010880:Piperidines; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin