A New Series of Orally Bioavailable Chemokine Receptor 9 (CCR9) Antagonists; Possible Agents for the Treatment of Inflammatory Bowel Disease

Chemokine
receptor 9 (CCR9), a cell surface chemokine receptor
which belongs to the G protein-coupled receptor, 7-trans-membrane
superfamily, is expressed on lymphocytes in the circulation and is
the key chemokine receptor that enables these cells to target the
intestine. It has been proposed that CCR9 antagonism represents a
means to prevent the aberrant immune response of inflammatory bowel
disease in a localized and disease specific manner and one which is
accessible to small molecule approaches. One possible reason why clinical
studies with vercirnon, a prototype CCR9 antagonist, were not successful
may be due to a relatively poor pharmacokinetic (PK) profile for the
molecule. We wish to describe work aimed at producing new, orally
active CCR9 antagonists based on the 1,3-dioxoisoindoline skeleton.
This study led to a number of compounds that were potent in the nanomolar
range and which, on optimization, resulted in several possible preclinical
development candidates with excellent PK properties.