Identification of novel azaindazole CCR1 antagonist clinical candidates

Christian Harcken; Daniel Kuzmich; Brain Cook; Can Mao; Darren Disalvo; Hossein Razavi; Alan Swinamer; Pingrong Liu; Qiang Zhang; Alison Kukulka; Donna Skow; Mita Patel; Monica Patel; Kimberly Fletcher; Tara Sherry; David Joseph; Dustin Smith; Melissa Canfield; Donald Souza; Matthew Bogdanffy; Karen Berg; Maryanne Brown

doi:10.1016/j.bmcl.2018.12.024

Identification of novel azaindazole CCR1 antagonist clinical candidates

Bioorg Med Chem Lett. 2019 Feb 1;29(3):441-448. doi: 10.1016/j.bmcl.2018.12.024. Epub 2018 Dec 13.

Authors

Christian Harcken¹, Daniel Kuzmich², Brain Cook², Can Mao², Darren Disalvo², Hossein Razavi², Alan Swinamer², Pingrong Liu², Qiang Zhang², Alison Kukulka³, Donna Skow³, Mita Patel⁴, Monica Patel⁴, Kimberly Fletcher⁴, Tara Sherry⁴, David Joseph⁴, Dustin Smith⁴, Melissa Canfield⁵, Donald Souza⁵, Matthew Bogdanffy⁶, Karen Berg⁵, Maryanne Brown⁵

Affiliations

¹ Medicinal Chemistry Department, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA. Electronic address: [email protected].
² Medicinal Chemistry Department, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
³ Compound Profiling Department, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
⁴ Drug Discovery Support Department, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
⁵ Immunology & Respiratory Disease Research Department, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
⁶ Non-Clinical Drug Safety Department, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.

PMID: 30595446
DOI: 10.1016/j.bmcl.2018.12.024

Abstract

Exploring various cyclization strategies, using a submicromolar pyrazole HTS screening hit 6 as a starting point, a novel indazole based CCR1 antagonist core was discovered. This report presents the design and SAR of CCR1 indazole and azaindazole antagonists leading to the identification of three development compounds, including 19e that was advanced to early clinical trials.

Keywords: CCR1; Chemokine receptors; Clinical compound; Indazole; Scaffold hopping.

MeSH terms

Aza Compounds / chemical synthesis
Aza Compounds / chemistry
Aza Compounds / pharmacology*
Dose-Response Relationship, Drug
Drug Design
Humans
Indazoles / chemical synthesis
Indazoles / chemistry
Indazoles / pharmacology*
Molecular Structure
Receptors, CCR1 / antagonists & inhibitors*
Receptors, CCR1 / metabolism
Structure-Activity Relationship

Substances

Aza Compounds
CCR1 protein, human
Indazoles
Receptors, CCR1