Rejected

Our previous scaffold-hopping attempts resulted in dihydropyrazino-benzimidazoles as metabotropic glutamate receptor-2 (mGluR2) positive allosteric modulators (PAMs) with suboptimal drug-like profiles. Here, we report an alternative fragment-based optimization strategy applied on the new dihydropyrazino-benzimidazolone scaffold. Analyzing published high-affinity mGluR2 PAMs, we used a pharmacophore-guided approach to identify suitable growing vectors and optimize the scaffold in these directions. This strategy resulted in a new fragment like lead () with improved druglike properties that were translated to sufficient pharmacokinetics and validated proof-of-concept studies in migraine. Gratifyingly, compound showed reasonable activity in the partial infraorbital nerve ligation, a migraine disease model that might open this indication for mGluR2 PAMs.

Osteoarthritis (OA) is a common degenerative joint disease blamed for pain and disability in the elderly. Galangin (GAL) is a natural flavonoid that exhibits anti-inflammatory properties in various inflammation diseases. However, the role of GAL in OA remains unclear. In this study, we investigate the role of GAL in the progress and development of OA in vitro and vivo. The results showed that IL-1β exposure resulted in increased expression of iNOS, COX-2, MMP1, MMP3, MMP13 and ADAMTS5 in rat chondrocytes. However, co-treatment with GAL significantly decreased theses inflammatory cytokines and catabolic factors expression. In addition, GAL reduced IL-1β-induced degradation of collagen II and aggrecan in chondrocytes. Furthermore, GAL significantly suppressed IL-1β-induced Akt phosphorylation and NF-κB activation in rat chondrocytes. In vivo, intra-articular injection of GAL could also reduce the cartilage degradation in the ACLT rat model. This study reveals galangin may act as a promising novel agent in the treatment of OA.

Microneedling promotes skin microlesions that lead to an inflammatory process, increasing cell proliferation, cell metabolism, and synthesis of collagen and elastin, therefore restoring skin integrity.

We investigated safety, tolerability, pharmacokinetics, and antitumor activity of the protein tyrosine kinase 7 (PTK7)-targeted, auristatin-based antibody-drug conjugate (ADC) PF-06647020/cofetuzumab pelidotin (NCT02222922).

Pruritus is an annoying symptom with an unclear pathogenesis accompanied by chronic cholestasis. This cross-sectional study was conducted to define the relationship between serum levels of presumed pruritogens (bile acids (BAs) and serotonin) and severity of pruritus in pediatric patients with chronic cholestatic liver disease.

Long-lasting insecticidal nets (LLINs) are the most widely used malaria prevention and control intervention in Africa. However, their effectiveness may vary depending on their local geographic coverage, ownership and use at household level. This study aimed at assessing LLINs ownership and use following mass distribution campaign in western Kenya.

Vapocoolant sprays are convenient forms of cold temperature analgesia. These sprays may not be suitable for all patients with particular concern for patients with sickle cell disease. To prevent any further cases from occurring, we propose adding a more specific cautionary statement to the manufacturer guidelines. We also hope that medical personnel can help patients with sickle cell avoid topical and environmental cold temperature triggers for sickle vaso-occlusive pain and reduce the suffering in this rare disease.

To provide an overview of the efficacy and safety of lemborexant in the treatment of insomnia disorder by assessing the currently available literature.

Pain is the foremost complication to chronic pancreatitis (CP), but no validated questionnaires for assessment exist. The COMPAT questionnaire includes all relevant pain dimensions in CP, but a short form is needed to make it usable in clinical practice.