title: A New Series of Orally Bioavailable Chemokine Receptor 9 (CCR9) Antagonists; Possible Agents for the Treatment of Inflammatory Bowel Disease.
abstract: 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.
authors.affiliation: Norgine Ltd , Norgine House, Widewater Place, Moorhall Road, Harefield, Uxbridge, UB9 6NS, United Kingdom.
authors.forename: S Barret
authors.initials: SB
authors.lastname: Kalindjian
authors.affiliation: Jubilant Biosys Limited , #96, Industrial Suburb, Second Stage, Yeshwanthpur, Bangalore 560022, India.
authors.forename: Sanjay V
authors.initials: SV
authors.lastname: Kadnur
authors.affiliation: Norgine Ltd , Norgine House, Widewater Place, Moorhall Road, Harefield, Uxbridge, UB9 6NS, United Kingdom.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Hewson
authors.affiliation: Jubilant Biosys Limited , #96, Industrial Suburb, Second Stage, Yeshwanthpur, Bangalore 560022, India.
authors.forename: Chandregowda
authors.initials: C
authors.lastname: Venkateshappa
authors.affiliation: Jubilant Biosys Limited , #96, Industrial Suburb, Second Stage, Yeshwanthpur, Bangalore 560022, India.
authors.forename: Suresh
authors.initials: S
authors.lastname: Juluri
authors.affiliation: Jubilant Biosys Limited , #96, Industrial Suburb, Second Stage, Yeshwanthpur, Bangalore 560022, India.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Kristam
authors.affiliation: Jubilant Biosys Limited , #96, Industrial Suburb, Second Stage, Yeshwanthpur, Bangalore 560022, India.
authors.forename: Bheemashankar
authors.initials: B
authors.lastname: Kulkarni
authors.affiliation: Jubilant Biosys Limited , #96, Industrial Suburb, Second Stage, Yeshwanthpur, Bangalore 560022, India.
authors.forename: Zainuddin
authors.initials: Z
authors.lastname: Mohammed
authors.affiliation: Jubilant Chemsys Limited , B-34 Sector-58, Noida 201301, India.
authors.forename: Rohit
authors.initials: R
authors.lastname: Saxena
authors.affiliation: Jubilant Biosys Limited , #96, Industrial Suburb, Second Stage, Yeshwanthpur, Bangalore 560022, India.
authors.forename: Vellarkad N
authors.initials: VN
authors.lastname: Viswanadhan
authors.affiliation: Jubilant Biosys Limited , #96, Industrial Suburb, Second Stage, Yeshwanthpur, Bangalore 560022, India.
authors.forename: Jayashree
authors.initials: J
authors.lastname: Aiyar
authors.affiliation: Norgine Ltd , Norgine House, Widewater Place, Moorhall Road, Harefield, Uxbridge, UB9 6NS, United Kingdom.
authors.forename: Donna
authors.initials: D
authors.lastname: McVey
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D060326:Chemistry Techniques, Synthetic; D002633:Chemotaxis / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy; D004195:Disease Models, Animal; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D054833:Isoindoles / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D008297:Male; D008810:Mice, Inbred C57BL; D054388:Receptors, CCR / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: C119309:CC chemokine receptor 9; C583420:CCX282-B; D054833:Isoindoles; D054388:Receptors, CCR; D013449:Sulfonamides