Solid-Phase Synthesis of Piperazinones via Disrupted Ugi Condensation

The first application of aziridine aldehyde dimers in solid-phase synthesis is reported. The solid-supported disrupted Ugi condensation between an aziridine aldehyde dimer, isonitrile, and backbone-anchored amino acids delivered <i>N</i>-acyl aziridine intermediates, which were reacted with nucleophiles to yield the corresponding piperazinones. Subsequent cleavage from the resin provided a diverse set of 2,3,6-trisubstituted piperazinones starting from various amino acids, aziridine aldehydes, and nucleophiles

Design and Synthesis of Potent, Selective Inhibitors of Matriptase

Matriptase is a member of the type II transmembrane serine protease family. Several studies have reported deregulated matriptase expression in several types of epithelial cancers, suggesting that matriptase constitutes a potential target for cancer therapy. We report herein a new series of slow, tight-binding inhibitors of matriptase, which mimic the P1–P4 substrate recognition sequence of the enzyme. Preliminary structure–activity relationships indicate that this benzothiazole-containing RQAR-peptidomimetic is a very potent inhibitor and possesses a good selectivity for matriptase versus other serine proteases. A molecular model was generated to elucidate the key contacts between inhibitor <b>1</b> and matriptase

Analysis of Subpocket Selectivity and Identification of Potent Selective Inhibitors for Matriptase and Matriptase‑2

We studied the factors affecting the selectivity of peptidomimetic inhibitors of the highly homologous proteases matriptase and matriptase-2 across subpockets using docking simulations. We observed that the farther away a subpocket is located from the catalytic site, the more pronounced its role in selectivity. As a result of our exhaustive virtual screening, we biochemically validated novel potent and selective inhibitors of both enzymes

Analysis of Subpocket Selectivity and Identification of Potent Selective Inhibitors for Matriptase and Matriptase‑2

We studied the factors affecting the selectivity of peptidomimetic inhibitors of the highly homologous proteases matriptase and matriptase-2 across subpockets using docking simulations. We observed that the farther away a subpocket is located from the catalytic site, the more pronounced its role in selectivity. As a result of our exhaustive virtual screening, we biochemically validated novel potent and selective inhibitors of both enzymes

Synthesis and Characterization of a Phosphate Prodrug of Isoliquiritigenin

Isoliquiritigenin (<b>1</b>) possesses a variety of biological activities in vitro. However, its poor aqueous solubility limits its use for subsequent in vivo experimentation. In order to enable the use of <b>1</b> for in vivo studies without the use of toxic carriers or cosolvents, a phosphate prodrug strategy was implemented relying on the availability of phenol groups in the molecule. In this study, a phosphate group was added to position C-4 of <b>1</b>, leading to the more water-soluble prodrug <b>2</b> and its ammonium salt <b>3</b>, which possesses increased stability compared to <b>2</b>. Herein are reported the synthesis, characterization, solubility, and stability of phosphate prodrug <b>3</b> in biological medium in comparison to <b>1</b>, as well as new results on its anti-inflammatory properties in vivo. As designed, the solubility of prodrug <b>3</b> was superior to that of the parent natural product <b>1</b> (9.6 mg/mL as opposed to 3.9 μg/mL). Prodrug <b>3</b> as an ammonium salt was also found to possess excellent stability as a solid and in aqueous solution, as opposed to its phosphoric acid precursor <b>2</b>

Optimization of the Potency and Pharmacokinetic Properties of a Macrocyclic Ghrelin Receptor Agonist (Part I): Development of Ulimorelin (TZP-101) from Hit to Clinic

High-throughput screening of Tranzyme Pharma’s proprietary macrocycle library using the aequorin Ca²⁺-bioluminescence assay against the human ghrelin receptor (GRLN) led to the discovery of novel agonists against this G-protein coupled receptor. Early hits such as <b>1</b> (<i>K</i>_i = 86 nM, EC₅₀ = 134 nM) though potent in vitro displayed poor pharmacokinetic properties that required optimization. While such macrocycles are not fully rule-of-five compliant, principally due to their molecular weight and clogP, optimization of their pharmacokinetic properties proved feasible largely through conformational rigidification. Extensive SAR led to the identification of <b>2</b> (<i>K</i>_i = 16 nM, EC₅₀ = 29 nM), also known as ulimorelin or TZP-101, which has progressed to phase III human clinical trials for the treatment of postoperative ileus. X-ray structure and detailed NMR studies indicated a rigid peptidomimetic portion in <b>2</b> that is best defined as a nonideal type-I′ β-turn. Compound <b>2</b> is 24% orally bioavailable in both rats and monkeys. Despite its potency, in vitro and in gastric emptying studies, <b>2</b> did not induce growth hormone (GH) release in rats, thus demarcating the GH versus GI pharmacology of GRLN