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.
The medicinal chemistry and preclinical biology of imidazopyridine-based inhibitors of diacylglycerol acyltransferase 2 (DGAT2) is described. A screening hit 1 with low lipophilic efficiency (LipE) was optimized through two key structural modifications: (1) identification of the pyrrolidine amide group for a significant LipE improvement, and (2) insertion of a sp(3)-hybridized carbon center in the core of the molecule for simultaneous improvement of N-glucuronidation metabolic liability and off-target pharmacology. The preclinical candidate 9 (PF-06424439) demonstrated excellent ADMET properties and decreased circulating and hepatic lipids when orally administered to dyslipidemic rodent models.
Full details are provided for an exceedingly practical
method to synthesize d- and l-α-amino
acids,
N-protected α-amino acids, and
N-methyl-α-amino acids, employing as a key step the
asymmetric alkylation of
pseudoephedrine glycinamide (1) or pseudoephedrine
sarcosinamide (2). Practical procedures for the
synthesis of 1
and 2 from pseudoephedrine and glycine methyl ester or
sarcosine methyl ester, respectively, are presented.
Optimum
protocols for the enolization and subsequent alkylation of 1
and 2 are described. Alkylation reactions of
1 and 2 are
found to be quite efficient with a wide range of alkyl halide
substrates, and the products are formed with high
diastereoselectivity. The products of these alkylation reactions
are hydrolyzed efficiently and with little to no
racemization simply by heating in water or water−dioxane mixtures.
This protocol provides an exceedingly practical
method for the preparation of salt-free α-amino acids of high
enantiomeric purity. Alternatively, the alkylation
products may be hydrolyzed in high yield and with little to no
racemization by heating with aqueous sodium hydroxide.
The alkaline hydrolyzate can then be treated with an acylating
reagent to provide directly highly enantiomerically
enriched N-protected derivatives such as N-Boc
and N-Fmoc. Key features necessary for the successful
execution
of these experimental procedures are identified.
The microsolvated
state of a molecule, represented by its interactions
with only a small number of solvent molecules, can play a key role
in determining the observable bulk properties of the molecule. This
is especially true in cases where strong local hydrogen bonding exists
between the molecule and the solvent. One method that can probe the
microsolvated states of charged molecules is differential mobility
spectrometry (DMS), which rapidly interrogates an ion’s transitions
between a solvated and desolvated state in the gas phase (i.e., few
solvent molecules present). However, can the results of DMS analyses
of a class of molecules reveal information about the bulk physicochemical
properties of those species? Our findings presented here show that
DMS behaviors correlate strongly with the measured solution phase
pKa and pKb values, and cell permeabilities of a set of structurally related
drug molecules, even yielding high-resolution discrimination between
isomeric forms of these drugs. This is due to DMS’s ability to separate species based upon only subtle (yet
predictable) changes in structure: the same subtle changes that can
influence isomers’ different bulk properties. Using 2-methylquinolin-8-ol
as the core structure, we demonstrate how DMS shows promise for rapidly
and sensitively probing the physicochemical properties of molecules,
with particular attention paid to drug candidates at the early stage
of drug development. This study serves as a foundation upon which
future drug molecules of different structural classes could be examined.
Acetyl-CoA
carboxylase (ACC) inhibitors offer significant potential
for the treatment of type 2 diabetes mellitus (T2DM), hepatic steatosis,
and cancer. However, the identification of tool compounds suitable
to test the hypothesis in human trials has been challenging. An advanced
series of spirocyclic ketone-containing ACC inhibitors recently reported
by Pfizer were metabolized in vivo by ketone reduction, which complicated
human pharmacology projections. We disclose that this metabolic reduction
can be greatly attenuated through introduction of steric hindrance
adjacent to the ketone carbonyl. Incorporation of weakly basic functionality
improved solubility and led to the identification of 9 as a clinical candidate for the treatment of T2DM. Phase I clinical
studies demonstrated dose-proportional increases in exposure, single-dose
inhibition of de novo lipogenesis (DNL), and changes in indirect calorimetry
consistent with increased whole-body fatty acid oxidation. This demonstration
of target engagement validates the use of compound 9 to
evaluate the role of DNL in human disease.
Myeloperoxidase (MPO) is a heme peroxidase that catalyzes the production of hypochlorous acid. Clinical evidence suggests a causal role for MPO in various autoimmune and inflammatory disorders including vasculitis and cardiovascular and Parkinson's diseases, implying that MPO inhibitors may represent a therapeutic treatment option. Herein, we present the design, synthesis, and preclinical evaluation of N1-substituted-6-arylthiouracils as potent and selective inhibitors of MPO. Inhibition proceeded in a time-dependent manner by a covalent, irreversible mechanism, which was dependent upon MPO catalysis, consistent with mechanism-based inactivation. N1-Substituted-6-arylthiouracils exhibited low partition ratios and high selectivity for MPO over thyroid peroxidase and cytochrome P450 isoforms. N1-Substituted-6-arylthiouracils also demonstrated inhibition of MPO activity in lipopolysaccharide-stimulated human whole blood. Robust inhibition of plasma MPO activity was demonstrated with the lead compound 2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999, 8) upon oral administration to lipopolysaccharide-treated cynomolgus monkeys. On the basis of its pharmacological and pharmacokinetic profile, PF-06282999 has been advanced to first-in-human pharmacokinetic and safety studies.
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