2,4,6-Triaminopyrimidine as a Novel Hinge Binder in a Series of PI3Kδ Selective Inhibitors

Leena Patel; Jayaraman Chandrasekhar; Jerry Evarts; Aaron C Haran; Carmen Ip; Joshua A Kaplan; Musong Kim; David Koditek; Latesh Lad; Eve-Irene Lepist; Mary E McGrath; Nikolai Novikov; Stephane Perreault; Kamal D Puri; John R Somoza; Bart H Steiner; Kirk L Stevens; Joseph Therrien; Jennifer Treiberg; Armando G Villaseñor; Arthur Yeung; Gary Phillips

doi:10.1021/acs.jmedchem.6b00213

2,4,6-Triaminopyrimidine as a Novel Hinge Binder in a Series of PI3Kδ Selective Inhibitors

J Med Chem. 2016 Apr 14;59(7):3532-48. doi: 10.1021/acs.jmedchem.6b00213. Epub 2016 Mar 29.

Authors

Leena Patel^{1

2}, Jayaraman Chandrasekhar^{1

2}, Jerry Evarts^{1

2}, Aaron C Haran^{1

2}, Carmen Ip^{1

2}, Joshua A Kaplan^{1

2}, Musong Kim^{1

2}, David Koditek^{1

2}, Latesh Lad^{1

2}, Eve-Irene Lepist^{1

2}, Mary E McGrath^{1

2}, Nikolai Novikov^{1

2}, Stephane Perreault^{1

2}, Kamal D Puri^{1

2}, John R Somoza^{1

2}, Bart H Steiner^{1

2}, Kirk L Stevens^{1

2}, Joseph Therrien^{1

2}, Jennifer Treiberg^{1

2}, Armando G Villaseñor^{1

2}, Arthur Yeung^{1

2}, Gary Phillips^{1

2}

Affiliations

¹ Gilead Sciences, Inc. , 199 E Blaine Street, Seattle, Washington 98102, United States.
² Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.

PMID: 26980109
DOI: 10.1021/acs.jmedchem.6b00213

Abstract

Inhibition of phosphoinositide 3-kinase δ (PI3Kδ) is an appealing target for several hematological malignancies and inflammatory diseases. Herein, we describe the discovery and optimization of a series of propeller shaped PI3Kδ inhibitors comprising a novel triaminopyrimidine hinge binder. Combinations of electronic and structural strategies were employed to mitigate aldehyde oxidase mediated metabolism. This medicinal chemistry effort culminated in the identification of 52, a potent and highly selective inhibitor of PI3Kδ that demonstrates efficacy in a rat model of arthritis.

MeSH terms

Animals
Arthritis, Experimental / chemically induced
Arthritis, Experimental / drug therapy*
Arthritis, Experimental / enzymology
B-Lymphocytes / cytology
B-Lymphocytes / drug effects
B-Lymphocytes / enzymology
Cells, Cultured
Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
Collagen / toxicity
Crystallography, X-Ray
Disease Models, Animal
Female
Hepatocytes / drug effects
Hepatocytes / enzymology
Humans
Microsomes, Liver / drug effects
Microsomes, Liver / enzymology
Models, Molecular
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemistry*
Pyrimidines / pharmacokinetics
Pyrimidines / pharmacology*
Quinazolinones / chemistry
Quinazolinones / pharmacokinetics
Quinazolinones / pharmacology*
Rats
Rats, Inbred Lew
Tissue Distribution

Substances

2,4-diamino-6-(1-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile
Protein Kinase Inhibitors
Pyrimidines
Quinazolinones
2,4,6-triaminopyrimidine
Collagen
Class I Phosphatidylinositol 3-Kinases
PIK3CD protein, human