title: Discovery of an in Vivo Tool to Establish Proof-of-Concept for MAP4K4-Based Antidiabetic Treatment.
abstract: Recent studies in adipose tissue, pancreas, muscle, and macrophages suggest that MAP4K4, a serine/threonine protein kinase may be a viable target for antidiabetic drugs. As part of the evaluation of MAP4K4 as a novel antidiabetic target, a tool compound, 16 (PF-6260933) and a lead 17 possessing excellent kinome selectivity and suitable properties were delivered to establish proof of concept in vivo. The medicinal chemistry effort that led to the discovery of these lead compounds is described herein together with in vivo pharmacokinetic properties and activity in a model of insulin resistance.
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, External Research Solutions, Primary Pharmacology Group, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Ammirati
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, External Research Solutions, Primary Pharmacology Group, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Bagley
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, External Research Solutions, Primary Pharmacology Group, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Samit K
authors.initials: SK
authors.lastname: Bhattacharya
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, External Research Solutions, Primary Pharmacology Group, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Leonard
authors.initials: L
authors.lastname: Buckbinder
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, External Research Solutions, Primary Pharmacology Group, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Carlo
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, External Research Solutions, Primary Pharmacology Group, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Conrad
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, External Research Solutions, Primary Pharmacology Group, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Christian
authors.initials: C
authors.lastname: Cortes
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, External Research Solutions, Primary Pharmacology Group, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Dow
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, External Research Solutions, Primary Pharmacology Group, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Dowling
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, External Research Solutions, Primary Pharmacology Group, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Ayman
authors.initials: A
authors.lastname: El-Kattan
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, External Research Solutions, Primary Pharmacology Group, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Kristen
authors.initials: K
authors.lastname: Ford
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, External Research Solutions, Primary Pharmacology Group, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Cristiano R W
authors.initials: CR
authors.lastname: Guimarães
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, External Research Solutions, Primary Pharmacology Group, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: David
authors.initials: D
authors.lastname: Hepworth
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, External Research Solutions, Primary Pharmacology Group, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Jiao
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, External Research Solutions, Primary Pharmacology Group, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: LaPerle
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, External Research Solutions, Primary Pharmacology Group, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Shenping
authors.initials: S
authors.lastname: Liu
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, External Research Solutions, Primary Pharmacology Group, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Allyn
authors.initials: A
authors.lastname: Londregan
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, External Research Solutions, Primary Pharmacology Group, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Loria
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, External Research Solutions, Primary Pharmacology Group, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Mathiowetz
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, External Research Solutions, Primary Pharmacology Group, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Munchhof
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, External Research Solutions, Primary Pharmacology Group, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Suvi T M
authors.initials: ST
authors.lastname: Orr
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, External Research Solutions, Primary Pharmacology Group, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Donna N
authors.initials: DN
authors.lastname: Petersen
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, External Research Solutions, Primary Pharmacology Group, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, External Research Solutions, Primary Pharmacology Group, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Athanasia
authors.initials: A
authors.lastname: Skoura
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, External Research Solutions, Primary Pharmacology Group, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Smith
authors.affiliation: Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Research Unit, External Research Solutions, Primary Pharmacology Group, and Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
keywords: HGK; MAP4K4; MAP4K4 inhibitor; P-loop; PF-6260933; ZC1; kinase inhibitor