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Design and synthesis of novel 2,3-dihydro-1H-isoindoles with high affinity and selectivity for the dopamine D3 receptor

2001; Elsevier BV; Volume: 11; Issue: 5 Linguagem: Inglês

10.1016/s0960-894x(01)00037-3

1464-3405

Nigel Austin, Kim Y. Avenell, Izzy Boyfield, Clive L. Branch, Michael S. Hadley, Philip D. Jeffrey, Christopher N. Johnson, Gregor J. Macdonald, David J. Nash, Graham J. Riley, Alexander B. Smith, Geoffrey Stemp, Kevin M. Thewlis, Antonio Vong, Martyn Wood,

Pharmacogenetics and Drug Metabolism

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).