Synthesis and SAR of aminothiazole fused benzazepines as selective dopamine D2 partial agonists

Rebecca A Urbanek; Hui Xiong; Ye Wu; William Blackwell; Gary Steelman; Jim Rosamond; Steven S Wesolowski; James B Campbell; Minli Zhang; Becky Brockel; Daniel V Widzowski

doi:10.1016/j.bmcl.2012.11.023

Synthesis and SAR of aminothiazole fused benzazepines as selective dopamine D2 partial agonists

Bioorg Med Chem Lett. 2013 Jan 15;23(2):543-7. doi: 10.1016/j.bmcl.2012.11.023. Epub 2012 Nov 28.

Authors

Rebecca A Urbanek¹, Hui Xiong, Ye Wu, William Blackwell, Gary Steelman, Jim Rosamond, Steven S Wesolowski, James B Campbell, Minli Zhang, Becky Brockel, Daniel V Widzowski

Affiliation

¹ CNS Discovery, AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE, USA.

PMID: 23237836
DOI: 10.1016/j.bmcl.2012.11.023

Abstract

Dopamine (D(2)) partial agonists (D2PAs) have been regarded as a potential treatment for schizophrenia patients with expected better side effect profiles than currently marketed antipsychotics. Herein we report the synthesis and SAR of a series of aminothiazole fused benzazepines as selective D(2) partial agonists. These compounds have good selectivity, CNS drug-like properties and tunable D(2) partial agonism. One of the key compounds, 8h, has good in vitro/in vivo ADME characteristics, and is active in a rat amphetamine-induced locomotor activity model.

MeSH terms

Animals
Antipsychotic Agents / chemical synthesis
Antipsychotic Agents / chemistry
Antipsychotic Agents / pharmacology
Benzazepines / chemical synthesis*
Benzazepines / chemistry
Benzazepines / pharmacology*
Biological Assay
Disease Models, Animal
Dopamine Agonists / chemical synthesis*
Dopamine Agonists / chemistry
Dopamine Agonists / pharmacology*
Drug Partial Agonism
Humans
Inhibitory Concentration 50
Molecular Structure
Protein Binding / drug effects
Rats
Receptors, Dopamine D2 / agonists*
Structure-Activity Relationship

Substances

Antipsychotic Agents
Benzazepines
Dopamine Agonists
Receptors, Dopamine D2