Dopamine D1/D5 receptor antagonists with improved pharmacokinetics: design, synthesis, and biological evaluation of phenol bioisosteric analogues of benzazepine D1/D5 antagonists.
Benzazepines 1 and 2 (SCH 23390 and SCH 39166, respectively) are two classical benzazepine D1/D5 antagonists, with Ki values 1.4 and 1.2 nM, respectively. Compound 2 has been in human clinical trials for a variety of diseases, including schizophrenia, cocaine addition, and obesity. Both 1 and 2 displayed low plasma levels and poor oral bioavailability, due to rapid first-pass metabolism of the phenol moieties. Several heterocyclic systems containing an N-H hydrogen bond donor were synthesized and evaluated as phenol isosteres. The preference orientation of the hydrogen bond was established by comparison of analogues containing different NH vectors. Replacement of the phenol group of 2 with an indole ring generated the first potent D1/D5 antagonist 11b. Further optimization led to the synthesis of very potent benzimidazolones 19, 20 and benzothiazolone analogues 28, 29. These compounds have excellent selectivity over D2-D4 receptors, alpha2a receptor, and the 5-HT transporter. Compared to 2, these heterocyclic phenol isosteres showed much better pharmacokinetic profiles as demonstrated by rat plasma levels. In sharp contrast, similar phenolic replacements in 1 decreased the binding affinity dramatically, presumably due to a conformational change of the pendant phenyl group. However, one indazole compound 33 was identified as a potent D1/D5 ligand in this series.
Wu
Wen-Lian
WL
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. wen-lian.wu@spcorp.com
Burnett
Duane A
DA
Spring
Richard
R
Greenlee
William J
WJ
Smith
Michelle
M
Favreau
Leonard
L
Fawzi
Ahmad
A
Zhang
Hongtao
H
Lachowicz
Jean E
JE
D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D018492:Dopamine Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D015195:Drug Design; D008297:Male; D008958:Models, Molecular; D010636:Phenols / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors*; D050641:Receptors, Dopamine D5; D013329:Structure-Activity Relationship
D001552:Benzazepines; D018492:Dopamine Antagonists; C493607:Drd5 protein, rat; D010636:Phenols; D017447:Receptors, Dopamine D1; D050641:Receptors, Dopamine D5; D000242:Cyclic AMP