I. Discovery of a novel series of CXCR3 antagonists. Multiparametric optimization of N,N-disubstituted benzylamines

Imre Bata; Zsuzsanna Tömösközi; Péter Buzder-Lantos; Attila Vasas; Gábor Szeleczky; Sándor Bátori; Veronika Barta-Bodor; László Balázs; György G Ferenczy

doi:10.1016/j.bmcl.2016.10.035

I. Discovery of a novel series of CXCR3 antagonists. Multiparametric optimization of N,N-disubstituted benzylamines

Bioorg Med Chem Lett. 2016 Nov 15;26(22):5418-5428. doi: 10.1016/j.bmcl.2016.10.035. Epub 2016 Oct 15.

Authors

Imre Bata¹, Zsuzsanna Tömösközi², Péter Buzder-Lantos², Attila Vasas², Gábor Szeleczky², Sándor Bátori², Veronika Barta-Bodor², László Balázs², György G Ferenczy³

Affiliations

¹ Sanofi Co. Ltd, H-1045 Budapest, Tó u. 1-5, Hungary. Electronic address: batai@richter.hu.
² Sanofi Co. Ltd, H-1045 Budapest, Tó u. 1-5, Hungary.
³ Sanofi Co. Ltd, H-1045 Budapest, Tó u. 1-5, Hungary. Electronic address: ferenczy.gyorgy@med.semmelweis-univ.hu.

PMID: 27789137
DOI: 10.1016/j.bmcl.2016.10.035

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.

Keywords: CXCR3 antagonist; Caco-2 permeability; Chemokine receptor; Inflammatory disease; Microsomal stability.

MeSH terms

Animals
Benzylamines / chemistry*
Benzylamines / pharmacokinetics
Benzylamines / pharmacology*
Caco-2 Cells
Humans
Mice
Microsomes, Liver / metabolism
Models, Molecular
Receptors, CXCR3 / antagonists & inhibitors*
Receptors, CXCR3 / metabolism*
Structure-Activity Relationship

Substances

Benzylamines
Receptors, CXCR3