Design of selective COX-2 inhibitors in the (aza)indazole series. Chemistry, in vitro studies, radiochemistry and evaluations in rats of a [18F] PET tracer

Jonathan Elie; Johnny Vercouillie; Nicolas Arlicot; Lucas Lemaire; Rudy Bidault; Sylvie Bodard; Christel Hosselet; Jean-Bernard Deloye; Sylvie Chalon; Patrick Emond; Denis Guilloteau; Frédéric Buron; Sylvain Routier

doi:10.1080/14756366.2018.1501043

Design of selective COX-2 inhibitors in the (aza)indazole series. Chemistry, in vitro studies, radiochemistry and evaluations in rats of a [¹⁸F] PET tracer

J Enzyme Inhib Med Chem. 2019 Dec;34(1):1-7. doi: 10.1080/14756366.2018.1501043.

Authors

Jonathan Elie^{1

2}, Johnny Vercouillie^{2

3

4

5}, Nicolas Arlicot^{2

3

4

5}, Lucas Lemaire¹, Rudy Bidault², Sylvie Bodard², Christel Hosselet^{2

3}, Jean-Bernard Deloye^{3

6}, Sylvie Chalon², Patrick Emond², Denis Guilloteau^{2

3

4

5}, Frédéric Buron¹, Sylvain Routier¹

Affiliations

¹ a ICOA, UMR CNRS 7311 , University of Orleans , Orleans , France.
² b UMR 1253, iBrain , Université de Tours, Inserm , Tours , France.
³ c CERRP , Centre d'Etude et de Recherche sur les Radiopharmaceutiques , Tours , France.
⁴ d CHRU , de Tours , Tours , France.
⁵ e INSERM CIC 1415 , University of François-Rabelais de Tours , Tours , France.
⁶ f Biopôle Clermont-Limagne , Laboratoires Cyclopharma , Saint-Beauzire , France.

Abstract

A series of novel derivatives exhibiting high affinity and selectivity towards the COX-2 enzyme in the (aza) indazole series was developed. A short synthetic route involving a bromination/arylation sequence under microwave irradiation and direct C-H activation were established in the indazole and azaindazole series respectively. In vitro assays were conducted and structural modifications were carried out on these scaffolds to furnish compound 16 which exhibited effective COX-2 inhibitory activity, with IC₅₀ values of 0.409 µM and an excellent selectivity versus COX-1. Radiolabeling of this most potent derivative [¹⁸F]16 was achieved after boron ester release and the tracer was evaluated in vivo in a rat model of neuroinflammation. All chemistry, radiochemistry and biological experimental data are discussed.

Keywords: (aza)indazoles; Cyclooxygenase; NSAID; PET; boronic ester; neuroinflammation; radiolabeling.

MeSH terms

Animals
Aza Compounds / chemical synthesis
Aza Compounds / chemistry
Aza Compounds / pharmacology*
Cyclooxygenase 2 / metabolism*
Cyclooxygenase 2 Inhibitors / chemical synthesis
Cyclooxygenase 2 Inhibitors / chemistry
Cyclooxygenase 2 Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Fluorine Radioisotopes
Indazoles / chemical synthesis
Indazoles / chemistry
Indazoles / pharmacology*
Molecular Structure
Positron-Emission Tomography*
Radioactive Tracers
Radiopharmaceuticals / chemical synthesis
Radiopharmaceuticals / chemistry
Radiopharmaceuticals / pharmacology*
Rats
Structure-Activity Relationship

Substances

Aza Compounds
Cyclooxygenase 2 Inhibitors
Fluorine Radioisotopes
Indazoles
Radioactive Tracers
Radiopharmaceuticals
Cyclooxygenase 2

Grants and funding

This research was supported by grants from the Labex IRON [ANR-11-LABX-0018–01] and InMIND program which are associated to this work.