title: I. Discovery of a novel series of CXCR3 antagonists. Multiparametric optimization of N,N-disubstituted benzylamines.
abstract: N,N-Disubstituted benzylamine derivatives have been identified as CXCR3 antagonists. Compounds were optimized to improve affinity and selectivity, to increase metabolic stability in human and mouse liver microsomes, to increase Caco-2 permeability. Optimization was supported by monitoring physico-chemical properties using both experimental and computational means. Several compounds with double-digit nanomolar CXCR3 affinity, favorable selectivity, microsomal stability, Caco-2 permeability and human hepatocyte clearance have been identified.
authors: Sanofi Co. Ltd, H-1045 Budapest, Tó u. 1-5, Hungary. Electronic address: batai@richter.hu.
authors: Imre
authors: I
authors: Bata
authors: Sanofi Co. Ltd, H-1045 Budapest, Tó u. 1-5, Hungary.
authors: Zsuzsanna
authors: Z
authors: Tömösközi
authors: Sanofi Co. Ltd, H-1045 Budapest, Tó u. 1-5, Hungary.
authors: Péter
authors: P
authors: Buzder-Lantos
authors: Sanofi Co. Ltd, H-1045 Budapest, Tó u. 1-5, Hungary.
authors: Attila
authors: A
authors: Vasas
authors: Sanofi Co. Ltd, H-1045 Budapest, Tó u. 1-5, Hungary.
authors: Gábor
authors: G
authors: Szeleczky
authors: Sanofi Co. Ltd, H-1045 Budapest, Tó u. 1-5, Hungary.
authors: Sándor
authors: S
authors: Bátori
authors: Sanofi Co. Ltd, H-1045 Budapest, Tó u. 1-5, Hungary.
authors: Veronika
authors: V
authors: Barta-Bodor
authors: Sanofi Co. Ltd, H-1045 Budapest, Tó u. 1-5, Hungary.
authors: László
authors: L
authors: Balázs
authors: Sanofi Co. Ltd, H-1045 Budapest, Tó u. 1-5, Hungary. Electronic address: ferenczy.gyorgy@med.semmelweis-univ.hu.
authors: György G
authors: GG
authors: Ferenczy
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D018938:Caco-2 Cells; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D001596:Benzylamines; D054367:Receptors, CXCR3
keywords: CXCR3 antagonist; Caco-2 permeability; Chemokine receptor; Inflammatory disease; Microsomal stability