Design and synthesis of novel 2,3-dihydro-1H-isoindoles with high affinity and selectivity for the dopamine D3 receptor.
Starting from the tetrahydroisoquinoline SB-277011 1, a novel series of 5-substituted-2,3-dihydro-1H-isoindoles has been designed. Subsequent optimisation resulted in identification of 19, which has high affinity for the dopamine D3 receptor (pKi 8.3) and > or = 100-fold selectivity over other aminergic receptors. In rat studies 19 was brain penetrant with an excellent pharmacokinetic profile (oral bioavailability 77%, t1/2 5.2h).
Austin
N E
NE
SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, Essex, UK.
Avenell
K Y
KY
Boyfield
I
I
Branch
C L
CL
Hadley
M S
MS
Jeffrey
P
P
Johnson
C N
CN
Macdonald
G J
GJ
Nash
D J
DJ
Riley
G J
GJ
Smith
A B
AB
Stemp
G
G
Thewlis
K M
KM
Vong
A K
AK
Wood
M D
MD
D000818:Animals; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D018492:Dopamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011869:Radioligand Assay; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3
C493593:DRD3 protein, human; D018492:Dopamine Antagonists; C493595:Drd3 protein, rat; D007211:Indoles; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3