Amide
couplings are one of, if not the most common chemical reactions
performed in the pharmaceutical industry. Many amide bonds are generated
with the help of highly active peptide coupling reagents. These reagents
have garnered wide use in the pharmaceutical industry, but many contain
high-energy functional groups. As a result, significant time is spent
assessing the thermal stability of these reagents before scale-up
commences. This paper assesses the thermal stability of 45 common
peptide coupling reagents by differential scanning calorimetry and
accelerating rate calorimetry. Those compounds which flagged as potentially
impact-sensitive or potentially explosive were tested by drop hammer
and explosivity screening techniques. The data are presented in an
effort to drive the development of these reactions toward the use
of one of the more thermally stable reagents.
Aqueous phosphoric acid (85 wt %) is an effective, environmentally benign reagent for the deprotection of tert-butyl carbamates, tert-butyl esters, and tert-butyl ethers. The reaction conditions are mild and offer good selectivity in the presence of other acid-sensitive groups, including CBZ carbamates, azetidine, benzyl and methyl esters, TBDMS, and methyl phenyl ethers. The mildness of the reaction is further demonstrated in the synthesis of clarithromycin derivative, in which a tert-butyl ester is removed in the presence of cyclic carbamate, lactone, ketal, acetate ester, and epimerizable methyl ketone functionalities. The reaction preserves the stereochemical integrity of the substrates. The reactions are high yielding, and the workup is convenient.
Increased fructose consumption and its subsequent metabolism have been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin resistance in humans. Since ketohexokinase (KHK) is the principal enzyme responsible for fructose metabolism, identification of a selective KHK inhibitor may help to further elucidate the effect of KHK inhibition on these metabolic disorders. Until now, studies on KHK inhibition with small molecules have been limited due to the lack of viable in vivo pharmacological tools. Herein we report the discovery of 12, a selective KHK inhibitor with potency and properties suitable for evaluating KHK inhibition in rat models. Key structural features interacting with KHK were discovered through fragment-based screening and subsequent optimization using structure-based drug design, and parallel medicinal chemistry led to the identification of pyridine 12.
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