Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3-Kinase δ for the Treatment of Respiratory Disease

Kenneth Down; Augustin Amour; Ian R Baldwin; Anthony W J Cooper; Angela M Deakin; Leigh M Felton; Stephen B Guntrip; Charlotte Hardy; Zoë A Harrison; Katherine L Jones; Paul Jones; Suzanne E Keeling; Joelle Le; Stefano Livia; Fiona Lucas; Christopher J Lunniss; Nigel J Parr; Ed Robinson; Paul Rowland; Sarah Smith; Daniel A Thomas; Giovanni Vitulli; Yoshiaki Washio; J Nicole Hamblin

doi:10.1021/acs.jmedchem.5b00767

Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3-Kinase δ for the Treatment of Respiratory Disease

J Med Chem. 2015 Sep 24;58(18):7381-99. doi: 10.1021/acs.jmedchem.5b00767. Epub 2015 Sep 3.

Authors

Kenneth Down^{1

2

3}, Augustin Amour^{1

2

3}, Ian R Baldwin^{1

2

3}, Anthony W J Cooper^{1

2

3}, Angela M Deakin^{1

2

3}, Leigh M Felton^{1

2

3}, Stephen B Guntrip^{1

2

3}, Charlotte Hardy^{1

2

3}, Zoë A Harrison^{1

2

3}, Katherine L Jones^{1

2

3}, Paul Jones^{1

2

3}, Suzanne E Keeling^{1

2

3}, Joelle Le^{1

2

3}, Stefano Livia^{1

2

3}, Fiona Lucas^{1

2

3}, Christopher J Lunniss^{1

2

3}, Nigel J Parr^{1

2

3}, Ed Robinson^{1

2

3}, Paul Rowland^{1

2

3}, Sarah Smith^{1

2

3}, Daniel A Thomas^{1

2

3}, Giovanni Vitulli^{1

2

3}, Yoshiaki Washio^{1

2

3}, J Nicole Hamblin^{1

2

3}

Affiliations

¹ Refractory Respiratory Inflammation DPU, and ‡Allergic Inflammation DPU, Respiratory Therapeutic Area, GlaxoSmithKline R&D , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
² Molecular Discovery Research, ∥Biological Sciences, and ⊥Computational Chemistry, Platform Technology & Science, GlaxoSmithKline R&D , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
³ Experimental Medicine Unit, and ∇Epinova DPU, ImmunoInflammation Therapeutic Area, GlaxoSmithKline R&D , Gunnels Wood Road, Stevenage, SG1 2NY, U.K.

PMID: 26301626
DOI: 10.1021/acs.jmedchem.5b00767

Abstract

Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.

MeSH terms

Administration, Inhalation
Animals
Asthma / drug therapy
Female
Humans
Indazoles / chemistry*
Indazoles / pharmacokinetics
Indazoles / pharmacology
Indoles
Isoenzymes / antagonists & inhibitors
Male
Microsomes / metabolism
Molecular Docking Simulation
Ovalbumin / immunology
Oxazoles / chemistry*
Oxazoles / pharmacokinetics
Oxazoles / pharmacology
Phosphoinositide-3 Kinase Inhibitors*
Piperazines
Pneumonia / drug therapy
Pneumonia / immunology
Pulmonary Disease, Chronic Obstructive / drug therapy
Rabbits
Rats
Rats, Sprague-Dawley
Respiratory Tract Diseases / drug therapy*
Stereoisomerism
Structure-Activity Relationship
Sulfonamides / chemistry*
Sulfonamides / pharmacokinetics
Sulfonamides / pharmacology
Th2 Cells / immunology

Substances

GSK2292767
Indazoles
Indoles
Isoenzymes
Oxazoles
Phosphoinositide-3 Kinase Inhibitors
Piperazines
Sulfonamides
Ovalbumin
Nemiralisib

Associated data

PDB/5AE8
PDB/5AE9