5 research outputs found
Novel Inhibitors of Nicotinamide-<i>N</i>-Methyltransferase for the Treatment of Metabolic Disorders
Nicotinamide-N-methyltransferase (NNMT) is a cytosolic enzyme catalyzing the transfer of a methyl group from S-adenosyl-methionine (SAM) to nicotinamide (Nam). It is expressed in many tissues including the liver, adipose tissue, and skeletal muscle. Its expression in several cancer cell lines has been widely discussed in the literature, and recent work established a link between NNMT expression and metabolic diseases. Here we describe our approach to identify potent small molecule inhibitors of NNMT featuring different binding modes as elucidated by X-ray crystallographic studies
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