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.
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 the 1 subunit. After confirming that human and rodent kidney predominately express AMPK1, 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.
Increased fructose
consumption and its subsequent metabolism have
been implicated in metabolic disorders such as nonalcoholic fatty
liver disease and steatohepatitis (NAFLD/NASH) and insulin resistance.
Ketohexokinase (KHK) converts fructose to fructose-1-phosphate (F1P)
in the first step of the metabolic cascade. Herein we report the discovery
of a first-in-class KHK inhibitor, PF-06835919 (8), currently
in phase 2 clinical trials. The discovery of 8 was built
upon our originally reported, fragment-derived lead 1 and the recognition of an alternative, rotated binding mode upon
changing the ribose-pocket binding moiety from a pyrrolidinyl to an
azetidinyl ring system. This new binding mode enabled efficient exploration
of the vector directed at the Arg-108 residue, leading to the identification
of highly potent 3-azabicyclo[3.1.0]hexane acetic acid-based KHK inhibitors
by combined use of parallel medicinal chemistry and structure-based
drug design.
A palladium-catalyzed one-step synthesis of (hetero)aryl alkyl sulfones from (hetero)arylboronic acids, potassium metabisulfite, and unactivated or activated alkylhalides is described. This transformation is of broad scope, occurs under mild conditions, and employs readily available reactants. A stoichiometric experiment has led to the isolation of a catalytically active dimeric palladium sulfinate complex, which was characterized by X-ray diffraction analysis.
Heterocyclic sulfinates
are effective reagents in palladium-catalyzed
coupling reactions with aryl and heteroaryl halides, often providing
high yields of the targeted biaryl. However, the preparation and purification
of complex heterocylic sulfinates can be problematic. In addition,
sulfinate functionality is not tolerant of the majority of synthetic
transformations, making these reagents unsuitable for multistep elaboration.
Herein, we show that heterocyclic allylsulfones can function as latent
sulfinate reagents and, when treated with a Pd(0) catalyst and an
aryl halide, undergo deallylation, followed by efficient desulfinylative
cross-coupling. A broad range of allyl heteroarylsulfones are conveniently
prepared, using several complementary routes, and are shown to be
effective coupling partners with a variety of aryl and heteroaryl
halides. We demonstrate that the allylsulfone functional group can
tolerate a range of standard synthetic transformations, including
orthogonal C- and N-coupling reactions, allowing multistep elaboration.
The allylsulfones are successfully coupled with a variety of medicinally
relevant substrates, demonstrating their applicability in demanding
cross-coupling transformations. In addition, pharmaceutical agents
crizotinib and etoricoxib were prepared using allyl heteroaryl sulfone
coupling partners, further demonstrating the utility of these new
reagents.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.