Design and synthesis of trans-3-(2-(4-((3-(3-(5-methyl-1,2,4-oxadiazolyl))- phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SB-414796): a potent and selective dopamine D3 receptor antagonist.
At their clinical doses, current antipsychotic agents share the property of both dopamine D(2) and D(3) receptor blockade. However, a major disadvantage of many current medications are the observed extrapyramidal side-effects (EPS), postulated to arise from D(2) receptor antagonism. Consequently, a selective dopamine D(3) receptor antagonist could offer an attractive antipsychotic therapy, devoid of the unwanted EPS. Using SAR information gained in two previously reported series of potent and selective D(3) receptor antagonists, as exemplified by the 2,3,4,5-tetrahydro-1H-3-benzazepine 10 and the 2,3-dihydro-1H-isoindoline 11, a range of 7-sulfonyloxy- and 7-sulfonylbenzazepines has been prepared. Compounds of this type combined a high level of D(3) affinity and selectivity vs D(2) with an excellent pharmacokinetic profile in the rat. Subsequent optimization of this series to improve selectivity over a range of receptors and reduce cytochrome P450 inhibitory potential gave trans-3-(2-(4-((3-(3-(5-methyl-1,2,4-oxidiazolyl))phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (58, SB-414796). This compound is a potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and is CNS penetrant in the rat. Subsequent evaluation in the rat has shown that 58 preferentially reduces firing of dopaminergic cells in the ventral tegmental area (A10) compared to the substantia nigra (A9), an observation consistent with a prediction for atypical antipsychotic efficacy. In a separate study, 58 has been shown to block expression of the conditioned place preference (CPP) response to cocaine in male rats, suggesting that it may also have a role in the treatment of cue-induced relapse in drug-free cocaine addicts.
GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK. Gregor_J_Macdonald@gsk.com
Gregor J
GJ
Macdonald
Clive L
CL
Branch
Michael S
MS
Hadley
Christopher N
CN
Johnson
David J
DJ
Nash
Alexander B
AB
Smith
Geoffrey
G
Stemp
Kevin M
KM
Thewlis
Antonio K K
AK
Vong
Nigel E
NE
Austin
Phillip
P
Jeffrey
Kim Y
KY
Winborn
Izzy
I
Boyfield
Jim J
JJ
Hagan
Derek N
DN
Middlemiss
Charlie
C
Reavill
Graham J
GJ
Riley
Jeannette M
JM
Watson
Martyn
M
Wood
Steve G
SG
Parker
Charles R
CR
Ashby
D000200:Action Potentials / Q000187:drug effects; D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001552:Benzazepines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D016466:CHO Cells; D002375:Catalepsy / Q000139:chemically induced; D003042:Cocaine / Q000494:pharmacology; D003214:Conditioning, Classical / Q000187:drug effects; D006224:Cricetinae; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D015195:Drug Design; D006801:Humans; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D011388:Prolactin / Q000097:blood; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3; D013329:Structure-Activity Relationship; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D013450:Sulfones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects / Q000502:physiology
C479684:3-(2-(4-((3-(3-(5-methyl-1,2,4-oxadiazolyl))phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-benzazepine; D014150:Antipsychotic Agents; D001552:Benzazepines; C493593:DRD3 protein, human; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; C493595:Drd3 protein, rat; D050637:Receptors, Dopamine D3; D013450:Sulfones; D011388:Prolactin; D003042:Cocaine; D004298:Dopamine