PF-06409577 |
| カタログ番号GC19286 |
PF-06409577 は、7 nM の EC50 を持つ AMPK α1β1γ1 アイソフォームの強力かつ選択的なアロステリック活性化剤です。
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Cas No.: 1467057-23-3
Sample solution is provided at 25 µL, 10mM.
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PF-06409577 is a potent and selective allosteric activator of AMPK α1β1γ1 isoform with an EC50 of 7 nM.
PF-06409577 possesses similar potency toward the human and rat α1β1γ1 isoforms. In broad panel screening against other receptors, channels, PDEs and kinases, PF-06409577 exhibits minimal off-target pharmacology. PF-06409577 shows no detectable inhibition of hERG in a patch-clamp assay (100 uM) and is not an inhibitor (IC50>100 uM) of the microsomal activities of major human cytochrome P450 isoforms[1].
PF-06409577 demonstrates moderate plasma clearance in rats, dogs, and monkeys, and is well distributed with steady state distribution volume. Following oral administration of crystalline PF-06409577 in 0.5% methylcellulose suspension, PF-06409577 is rapidly absorbed in rats, dogs, and monkeys. The corresponding oral bioavailability values in rats, dogs, and monkeys, are 15%, 100%, and 59%, respectively. Dose responsive increases in pAMPK relative to total AMPK (tAMPK) in whole kidney tissue are observed with a maximal 3.8-fold response at 300 mg/kg PF-06409577 treatment[1]. Oral administration of PF-06409577 (10, 30, and 100 mg/kg QD) results in dose-dependent reductions in proteinuria in the obese ZSF1 animals, with greater than 2-fold reduction in 24-hour urinary albumin loss compared to vehicle control after 60 days of treatment[1].
References:
[1]. Cameron KO, et al. Discovery and Preclinical Characterization of 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic Acid (PF-06409577), a Direct Activator of Adenosine Monophosphate-activated Protein Kinase (AMPK), for the Potential Treatment of Diabetic Nephropathy. J Med Chem. 2016 Sep 8;59(17):8068-81.
[2]. Salatto CT, et al. Selective Activation of AMPK β1-Containing Isoforms Improves Kidney Function in a Rat Model of Diabetic Nephropathy. J Pharmacol Exp Ther. 2017 May;361(2):303-311.
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