PF-06409577

• CAT Number: I008684
• CAS Number: 1467057-23-3
• Molecular Formula: C19H16ClNO3
• Molecular Weight: 341.791
• Purity: ≥95%
• Solubility: Soluble in DMSO
• Storage: 0 - 4 °C for short term, or -20 °C for long term

PF-06409577 (Cat.No:I008684) is a potent and selective activator of 5′ adenosine monophosphate-activated protein kinase (AMPK) for the Potential Treatment of diabetic nephropathy. PF-06409577 has AMPK α1β1γ1 Kd=9.0 nM. AMPK α1β1γ1 EC50 = 7.0 nM; AMPK α1β2γ1 EC50 > 40000 nM. PF-06409577 showed efficacy in a preclinical model of diabetic nephropathy. Upon the basis of its potent and selective AMPK activation, low metabolic turnover in human hepatocytes, clean off-target profile, and favorable preclinical in vivo efficacy results, PF-06409577 was profiled in regulatory toxicology studies and was subsequently advanced to clinical trials to assess human pharmacokinetics and safety/ tolerability.

Reference

1:J Med Chem. 2016 Sep 8;59(17):8068-81. doi: 10.1021/acs.jmedchem.6b00866. Epub 2016 Aug 20. 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.Cameron KO,Kung DW,Kalgutkar AS,Kurumbail RG,Miller R,Salatto CT,Ward J,Withka JM,Bhattacharya SK,Boehm M,Borzilleri KA,Brown JA,Calabrese M,Caspers NL,Cokorinos E,Conn EL,Dowling MS,Edmonds DJ,Eng H,Fernando DP,Frisbie R,Hepworth D,Landro J,Mao Y,Rajamohan F,Reyes AR,Rose CR,Ryder T,Shavnya A,Smith AC,Tu M,Wolford AC,Xiao J, PMID: 27490827 DOI: 10.1021/acs.jmedchem.6b00866 Abstract: Adenosine monophosphate-activated protein kinase (AMPK) is a protein kinase involved in maintaining energy homeostasis within cells. On the basis of human genetic association data, AMPK activators were pursued for the treatment of diabetic nephropathy. Identification of an indazole amide high throughput screening (HTS) hit followed by truncation to its minimal pharmacophore provided an indazole acid lead compound. Optimization of the core and aryl appendage improved oral absorption and culminated in the identification of indole acid, PF-06409577 (7). Compound 7 was advanced to first-in-human trials for the treatment of diabetic nephropathy.