Time-resolved laser flash spectroscopy with transient detection by time-resolved UV−vis,
IR, and EPR has been employed to investigate the photochemistry and photophysics of a series of
derivatives of 2-hydroxy-2-methyl-1-phenyl propanone, a model photoinitiator for free radical polymerization. H, Cl, and F substituents at the para position promote the n,π* nature of the lowest triplet state
and favor fast and efficient α-cleavage from T1 upon irradiation. In contrast, dimethylamino and thioether
substitution in the para position of the benzoyl moiety change the configuration of the lowest triplet
states into a π,π* and are characterized by a lack of α-cleavage from T1. Alkoxy substitution in the para
position represents an intermediate for which α-cleavage occurs efficiently, but at a relatively slow rate.
Alkylation of the 2-hydroxy group promotes fast α-cleavage upon irradiation (picosecond time scale), in
contrast to the analogous ester derivative for which slow cleavage was observed (microsecond time scale).
The conclusions are consistent with phosphorescence characterization of the triplet states and are
supported by photopolymerization studies.
A guide for stabilization of pharmaceuticals to oxidation is presented. Literature is presented with an attempt to be a ready source for data and recommendations for formulators. Liquid and solid dosage forms are discussed with options including formulation changes, additives, and packaging documented. In particular, selection of and methods for use of antioxidants are discussed including recommended levels.
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.
We report the structure-activity relationships, design, and synthesis of the novel cannabinoid type 1 (CB1) receptor antagonist 3a (CP-945,598). Compound 3a showed subnanomolar potency at human CB1 receptors in binding (Ki = 0.7 nM) and functional assays (Ki = 0.12 nM). In vivo, compound 3a reversed cannabinoid agonist-mediated responses, reduced food intake, and increased energy expenditure and fat oxidation in rodents.
This literature review presents hydrolysis of active pharmaceutical ingredients as well as the effects on dosage form stability due to hydrolysis of excipients. Mechanisms and measurement methods are discussed and recommendations for formulation stabilization are listed.
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