Neurotherapeutic Potential of Water-Soluble pH-Responsive Prodrugs of EIDD-036 in Traumatic Brain Injury.

The C-20 oxime of progesterone, EIDD-036 (2), demonstrates neuroprotection and improved outcomes in animal models of traumatic brain injury (TBI). However, 2 suffers from poor solubility, which renders it unsuitable for rapid administration. Previous prodrugs of 2 aimed at improving solubility by incorporating enzymatically labile amino acid and phosphate ester promoieties. These approaches were effective but led to limitations with in vivo administration. Herein, we disclose a pH-responsive water-soluble prodrug strategy to improve exposure to 2 through enzyme-independent activation. Compound 13l was identified as a lead that exhibits water-solubility, stability in acidic solutions, and rapid conversion to 2 at physiological pH. Administration of 13l to rats resulted in a twofold increase in exposure to 2 compared to the previous generation phosphate prodrug, EIDD-1723 (6). In a rat model of TBI, treatment with 13l resulted in a significant decrease in cerebral edema when administered postinjury.

Facile synthesis of a C4-symmetrical inherently chiral calix[4]arene.

Inherently chiral calix[4]arenes with C4-symmetry are extremely rare and difficult to synthesise, severely hampering any effort to expand on their potential as chiral supramolecular catalysts and building blocks. Herein we report a reaction of a tetracarbamate calix[4]arene with NBS which results in a high yield of an inherently chiral calix[4]arenes with C4-symmetry. Furthermore, employing a chiral N-Boc proline moiety allows for separation of the diastereomers formed, thus obtaining the pure enantiomers after hydrolysis. The enantiomers could be assigned based on the CD spectra and DFT calculated values.

Targeting Her2-insYVMA with Covalent Inhibitors-A Focused Compound Screening and Structure-Based Design Approach.

Mutated or amplified Her2 serves as a driver of non-small cell lung cancer or mediates resistance toward the inhibition of its family member epidermal growth factor receptor with small-molecule inhibitors. To date, small-molecule inhibitors targeting Her2 which can be used in clinical routine are lacking, and therefore, the development of novel inhibitors was undertaken. In this study, the well-established pyrrolopyrimidine scaffold was modified with structural motifs identified from a screening campaign with more than 1600 compounds, which were applied against wild-type Her2 and its mutant variant Her2-A775_G776insYVMA. The resulting inhibitors were designed to covalently target a reactive cysteine in the binding site of Her2 and were further optimized by means of structure-based drug design utilizing a set of obtained complex crystal structures. In addition, the analysis of binding kinetics and absorption, distribution, metabolism, and excretion parameters as well as mass spectrometry experiments and western blot analysis substantiated our approach.

Inhibition of osimertinib-resistant epidermal growth factor receptor EGFR-T790M/C797S.

Precision medicine has revolutionized the treatment of patients in EGFR driven non-small cell lung cancer (NSCLC). Targeted drugs show high response rates in genetically defined subsets of cancer patients and markedly increase their progression-free survival as compared to conventional chemotherapy. However, recurrent acquired drug resistance limits the success of targeted drugs in long-term treatment and requires the constant development of novel efficient inhibitors of drug resistant cancer subtypes. Herein, we present covalent inhibitors of the drug resistant gatekeeper mutant EGFR-L858R/T790M based on the pyrrolopyrimidine scaffold. Biochemical and cellular characterization, as well as kinase selectivity profiling and western blot analysis, substantiate our approach. Moreover, the developed compounds possess high activity against multi drug resistant EGFR-L858R/T790M/C797S in biochemical assays due to their highly reversible binding character, that was revealed by characterization of the binding kinetics. In addition, we present the first X-ray crystal structures of covalent inhibitors in complex with C797S-mutated EGFR which provide detailed insight into their binding mode.