Discovery and optimization of potent and selective imidazopyridine and imidazopyridazine mTOR inhibitors

Emily A Peterson; Alessandro A Boezio; Paul S Andrews; Christiane M Boezio; Tammy L Bush; Alan C Cheng; Deborah Choquette; James R Coats; Adria E Colletti; Katrina W Copeland; Michelle DuPont; Russell Graceffa; Barbara Grubinska; Joseph L Kim; Richard T Lewis; Jingzhou Liu; Erin L Mullady; Michele H Potashman; Karina Romero; Paul L Shaffer; Mary K Stanton; John C Stellwagen; Yohannes Teffera; Shuyan Yi; Ti Cai; Daniel S La

doi:10.1016/j.bmcl.2012.06.033

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Discovery and optimization of potent and selective imidazopyridine and imidazopyridazine mTOR inhibitors

Journal article

Peer reviewed

Discovery and optimization of potent and selective imidazopyridine and imidazopyridazine mTOR inhibitors

Emily A Peterson, Alessandro A Boezio, Paul S Andrews, Christiane M Boezio, Tammy L Bush, Alan C Cheng, Deborah Choquette, James R Coats, Adria E Colletti, Katrina W Copeland, …

Bioorganic & medicinal chemistry letters, Vol.22(15), pp.4967-4974

08/01/2012

DOI: https://doi.org/10.1016/j.bmcl.2012.06.033

PMID: 22765895

Abstract

Imidazopyridazine

Imidazopyridine

Kinase inhibitor

mTOR

Oncology

mTOR is a critical regulator of cellular signaling downstream of multiple growth factors. The mTOR/PI3K/AKT pathway is frequently mutated in human cancers and is thus an important oncology target. Herein we report the evolution of our program to discover ATP-competitive mTOR inhibitors that demonstrate improved pharmacokinetic properties and selectivity compared to our previous leads. Through targeted SAR and structure-guided design, new imidazopyridine and imidazopyridazine scaffolds were identified that demonstrated superior inhibition of mTOR in cellular assays, selectivity over the closely related PIKK family and improved in vivo clearance over our previously reported benzimidazole series.

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Title: Discovery and optimization of potent and selective imidazopyridine and imidazopyridazine mTOR inhibitors
Creators: Emily A Peterson - Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA
Alessandro A Boezio - Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA
Paul S Andrews - Lead Discovery, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA
Christiane M Boezio - Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA
Tammy L Bush - Oncology Research, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA
Alan C Cheng - Amgen
Deborah Choquette - Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA
James R Coats - Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA
Adria E Colletti - Pharmacokinetics and Drug Metabolism, Amgen Inc., 360 Binney St., Cambridge, MA 02142,USA
Katrina W Copeland - Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA
Michelle DuPont - Oncology Research, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA
Russell Graceffa - Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA
Barbara Grubinska - Oncology Research, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA
Joseph L Kim - Molecular Structure, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA
Richard T Lewis - Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA
Jingzhou Liu - Pharmacokinetics and Drug Metabolism, Amgen Inc., 360 Binney St., Cambridge, MA 02142,USA
Erin L Mullady - Lead Discovery, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA
Michele H Potashman - Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA
Karina Romero - Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA
Paul L Shaffer - Molecular Structure, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA
Mary K Stanton - Pharmaceutics R&D, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA
John C Stellwagen - Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA
Yohannes Teffera - Molecular Structure, Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, USA
Shuyan Yi - Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA
Ti Cai - Oncology Research, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA
Daniel S La - Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA
Publication Details: Bioorganic & medicinal chemistry letters, Vol.22(15), pp.4967-4974
Publisher: Elsevier Ltd
Identifiers: 9924086498001921
Academic Unit: Rabb School of Continuing Studies, Division of Graduate Professional Studies
Language: English
Resource Type: Journal article

Discovery and optimization of potent and selective imidazopyridine and imidazopyridazine mTOR inhibitors

Abstract

UN Sustainable Development Goals (SDGs)

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