title: Selective Activation of AMPKβ1-Containing Isoforms Improves Kidney Function in a Rat Model of Diabetic Nephropathy.
abstract: Diabetic nephropathy remains an area of high unmet medical need, with current therapies that slow down, but do not prevent, the progression of disease. A reduced phosphorylation state of adenosine monophosphate-activated protein kinase (AMPK) has been correlated with diminished kidney function in both humans and animal models of renal disease. Here, we describe the identification of novel, potent, small molecule activators of AMPK that selectively activate AMPK heterotrimers containing theβ1 subunit. After confirming that human and rodent kidney predominately express AMPKβ1, we explore the effects of pharmacological activation of AMPK in the ZSF1 rat model of diabetic nephropathy. Chronic administration of these direct activators elevates the phosphorylation of AMPK in the kidney, without impacting blood glucose levels, and reduces the progression of proteinuria to a greater degree than the current standard of care, angiotensin-converting enzyme inhibitor ramipril. Further analyses of urine biomarkers and kidney tissue gene expression reveal AMPK activation leads to the modulation of multiple pathways implicated in kidney injury, including cellular hypertrophy, fibrosis, and oxidative stress. These results support the need for further investigation into the potential beneficial effects of AMPK activation in kidney disease.
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut christopher.t.salatto@pfizer.com.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Salatto
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: Russell A
authors.initials: RA
authors.lastname: Miller
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: Kimberly O
authors.initials: KO
authors.lastname: Cameron
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: Emily
authors.initials: E
authors.lastname: Cokorinos
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: Allan
authors.initials: A
authors.lastname: Reyes
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: Jessica
authors.initials: J
authors.lastname: Ward
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Calabrese
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: Ravi G
authors.initials: RG
authors.lastname: Kurumbail
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: Francis
authors.initials: F
authors.lastname: Rajamohan
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: Amit S
authors.initials: AS
authors.lastname: Kalgutkar
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: David A
authors.initials: DA
authors.lastname: Tess
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: Andre
authors.initials: A
authors.lastname: Shavnya
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: Nathan E
authors.initials: NE
authors.lastname: Genung
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: David J
authors.initials: DJ
authors.lastname: Edmonds
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: Aditi
authors.initials: A
authors.lastname: Jatkar
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Maciejewski
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: Marina
authors.initials: M
authors.lastname: Amaro
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: Harmeet
authors.initials: H
authors.lastname: Gandhok
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: Mara
authors.initials: M
authors.lastname: Monetti
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: Katherine
authors.initials: K
authors.lastname: Cialdea
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: Eliza
authors.initials: E
authors.lastname: Bollinger
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: John M
authors.initials: JM
authors.lastname: Kreeger
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Coskran
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Opsahl
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: Germaine G
authors.initials: GG
authors.lastname: Boucher
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Birnbaum
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: Paul
authors.initials: P
authors.lastname: DaSilva-Jardine
authors.affiliation: CVMET Research Unit (C.T.S., R.A.M., E.C., A.R., J.W., A.J., B.S.M., M.A., H.G., M.M., K.C., E.B., M.J.B., P.D.-J., T.R.), Worldwide Medicinal Chemistry (K.O.C., D.J.E.), and Pharmacokinetics, Dynamics, & Metabolism (A.S.K., D.A.T.), Pfizer Worldwide Research and Development, Cambridge, Massachusetts; and Worldwide Medicinal Chemistry (M.C., R.K., F.R., A.S., N.E.G.), and Drug Safety Research and Development (J.M.K., T.M.C., A.C.O., G.G.B.), Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: Tim
authors.initials: T
authors.lastname: Rolph
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000631:Aminopyridines / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D048429:Cell Size; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D005355:Fibrosis; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D007527:Isoenzymes / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007677:Kidney Function Tests; D008252:Macaca fascicularis; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D010766:Phosphorylation; D011507:Proteinuria / Q000188:drug therapy / Q000378:metabolism; D051381:Rats; D013045:Species Specificity
chemical_list: D000631:Aminopyridines; D020536:Enzyme Activators; D007211:Indoles; D007527:Isoenzymes; C000617641:PF-249; C000617640:PF-6409577; D055372:AMP-Activated Protein Kinases