The development of a gold(I)-catalyzed sulfination of aryl boronic acids is described. This transformation proceeds through an unprecedented mechanism which exploits the reactivity of gold(I)–heteroatom bonds to form sulfinate anions. Further in situ elaboration of the sulfinate intermediates leads to the corresponding sulfones and sulfonamides, two pharmacophores routinely encountered in drug discovery.
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.
Recent studies in adipose tissue, pancreas, muscle, and macrophages suggest that MAP4K4, a serine/threonine protein kinase may be a viable target for antidiabetic drugs. As part of the evaluation of MAP4K4 as a novel antidiabetic target, a tool compound, 16 (PF-6260933) and a lead 17 possessing excellent kinome selectivity and suitable properties were delivered to establish proof of concept in vivo. The medicinal chemistry effort that led to the discovery of these lead compounds is described herein together with in vivo pharmacokinetic properties and activity in a model of insulin resistance.
Peptide
agonists of the glucagon-like peptide-1 receptor (GLP-1R)
have revolutionized diabetes therapy, but their use has been limited
because they require injection. Herein, we describe the discovery
of the orally bioavailable, small-molecule, GLP-1R agonist PF-06882961
(danuglipron). A sensitized high-throughput screen was used to identify
5-fluoropyrimidine-based GLP-1R agonists that were optimized to promote
endogenous GLP-1R signaling with nanomolar potency. Incorporation
of a carboxylic acid moiety provided considerable GLP-1R potency gains
with improved off-target pharmacology and reduced metabolic clearance,
ultimately resulting in the identification of danuglipron. Danuglipron
increased insulin levels in primates but not rodents, which was explained
by receptor mutagensis studies and a cryogenic electron microscope
structure that revealed a binding pocket requiring a primate-specific
tryptophan 33 residue. Oral administration of danuglipron to healthy
humans produced dose-proportional increases in systemic exposure (NCT03309241).
This opens an opportunity for oral small-molecule therapies that target
the well-validated GLP-1R for metabolic health.
A series of low‐molecular‐weight, compact, and multifunctional cyclic alkenylsulfonyl fluorides were efficiently prepared from the corresponding alkenyl triflates. Palladium‐catalyzed sulfur dioxide insertion using the surrogate reagent DABSO effects sulfinate formation, before trapping with an F electrophile delivers the sulfonyl fluorides. A broad range of functional groups are tolerated, and a correspondingly large collection of derivatization reactions are possible on the products, including substitution at sulfur, conjugate addition, and N‐functionalization. Together, these attributes suggest that this method could find new applications in chemical biology.
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