Discovery and optimization of heteroaryl piperazines as potent and selective PI3Kδ inhibitors.

Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors High-Throughput Screening Assays / methods Humans Piperazines / pharmacology Protein Kinase Inhibitors / pharmacology Structure-Activity Relationship
PI3Kδ inhibitor Parallel medicinal chemistry Phosphoinositide 3-kinase δ Physicochemical properties Structure-activity relationship

Journal

Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377

Informations de publication

Date de publication:
01 01 2020
Historique:
received: 02 08 2019
revised: 16 09 2019
accepted: 21 09 2019
pubmed: 24 11 2019
medline: 9 2 2021
entrez: 24 11 2019
Statut: ppublish

Résumé

A high-throughput screening (HTS) campaign identified a class of heteroaryl piperazines with excellent baseline affinity and selectivity for phosphoinositide 3-kinase δ (PI3Kδ) over closely related isoforms. Rapid evaluation and optimization of structure-activity relationships (SAR) for this class, leveraging the modular nature of this scaffold, facilitated development of this hit class into a series of potent and selective inhibitors of PI3Kδ. This effort culminated in the identification of 29, which displayed excellent potency in enzyme and cell-based assays, as well as favorable pharmacokinetic and off-target profiles.

Identifiants

DOI: 10.1016/j.bmcl.2019.126715 PMID: 31757666
pubmed: 31757666
pii: S0960-894X(19)30673-0
doi: 10.1016/j.bmcl.2019.126715
pii:
doi:

Substances chimiques

Piperazines 0
Protein Kinase Inhibitors 0
Class I Phosphatidylinositol 3-Kinases EC 2.7.1.137

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

126715

Informations de copyright

Copyright © 2019 Elsevier Ltd. All rights reserved.

Auteurs

Hua Zhou (H)

Department of Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: hua_zhou2@merck.com.

Meredeth A McGowan (MA)

Department of Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: meredeth.mcgowan@merck.com.

Kathryn Lipford (K)

Department of Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.

Matthew Christopher (M)

Department of Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.

Xavier Fradera (X)

Department of Computational and Structural Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.

David Witter (D)

Department of Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.

Charles A Lesburg (CA)

Department of Computational and Structural Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.

Chaomin Li (C)

Department of Process Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.

Joey L Methot (JL)

Department of Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.

John Lampe (J)

Department of Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.

Abdelghani Achab (A)

Department of Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.

Lynsey Shaffer (L)

Department of In Vitro Pharmacology, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.

Peter Goldenblatt (P)

Department of In Vitro Pharmacology, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.

Sanjiv Shah (S)

Department of In Vitro Pharmacology, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.

Alan Bass (A)

Department of Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.

Gottfried Schroeder (G)

Department of In Vitro Pharmacology, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.

Dapeng Chen (D)

Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.

Haoyu Zeng (H)

Department of Safety Assessment and Laboratory Animal Resources, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.

Martin A Augustin (MA)

Proteros Biostructures GmbH, Bunsenstraße 7A, D-82152 Martinsreid, Germany.

Jason D Katz (JD)

Department of Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Phosphatidylinositol 3-kinases › Phosphatidylinositol-4-phosphate 3-kinase › Phosphatidylinositol 3-kinases de classe I › Discovery and optimization of heteroaryl...
questionsmedicales.fr › Techniques d'investigation › Tests de criblage à haut débit › Discovery and optimization of heteroaryl...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Discovery and optimization of heteroaryl...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pipérazines › Discovery and optimization of heteroaryl...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de protéines kinases › Discovery and optimization of heteroaryl...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Relation structure-activité › Discovery and optimization of heteroaryl...