Through the application of high-throughput nanoscale optimization, a mild, photocatalyzed, Minisci-like protocol was developed to access highly functionalized 1,3-disubstituted bicyclopentanes. The ...benzoate-isosteric compounds were prepared using a readily available organic photocatalyst, mitigating the need for precious metals. The strategy described furnished products in synthetically useful yields and was demonstrated to be executable in parallel medicinal chemistry format.
Many ecologists are interested in communicating science to the public and addressing societal concerns about environmental issues. Individual ecologists need to consider whether, when, and how this ...should be done. We propose that public outreach activities can be beneficial for ecologists at all stages of their career. There are diverse opportunities for such involvement, and these can vary enormously in terms of time and expertise required. Trends within the science of ecology, especially research focused on social-ecological systems, are likely to promote increased interactions with stakeholders and policy makers. To be effective in these interactions, ecologists should consider new approaches to communication and be aware of the potential roles scientists can play in public policy debates. Professional ecologists need to engage with non-scientific audiences; a review of such activities should be included in considerations for promotion, recognition, and awards, while also acknowledging variations in the inclinations and abilities of individual scientists. There are, however, few current standards for how much time ecologists should commit to public outreach, how time allocation might change over a career, or how to evaluate the quality of such activities. We ask ecologists to consider ways to evaluate the quality of interactions with the public and how to reward these efforts appropriately.
We wish to report a strategy that targets interleukin-2 inducible T cell kinase (Itk) with covalent inhibitors. Thus far, covalent inhibition of Itk has not been disclosed in the literature. ...Structure-based drug design was utilized to achieve low nanomolar potency of the disclosed series even at high ATP concentrations. Kinetic measurements confirmed an irreversible binding mode with off-rate half-lives exceeding 24 h and moderate on-rates. The analogues are highly potent in a cellular IP1 assay as well as in a human whole-blood (hWB) assay. Despite a half-life of approximately 2 h in resting primary T cells, the covalent inhibition of Itk resulted in functional silencing of the TCR pathway for more than 24 h. This prolonged effect indicates that covalent inhibition is a viable strategy to target the inactivation of Itk.
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Herein, we disclose a new series of TYK2/ JAK1 inhibitors based upon a 3.1.0 azabicyclic substituted pyrimidine scaffold. We illustrate the use of structure-based drug design for the ...initial design and subsequent optimization of this series of compounds. One advanced example 19 met program objectives for potency, selectivity and ADME, and demonstrated oral activity in the adjuvant-induced arthritis rat model.
Cytokine signaling is an important characteristic of autoimmune diseases. Many pro-inflammatory cytokines signal through the Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) ...pathway. JAK1 is important for the γ-common chain cytokines, interleukin (IL)-6, and type-I interferon (IFN) family, while TYK2 in addition to type-I IFN signaling also plays a role in IL-23 and IL-12 signaling. Intervention with monoclonal antibodies (mAbs) or JAK1 inhibitors has demonstrated efficacy in Phase III psoriasis, psoriatic arthritis, inflammatory bowel disease, and rheumatoid arthritis studies, leading to multiple drug approvals. We hypothesized that a dual JAK1/TYK2 inhibitor will provide additional efficacy, while managing risk by optimizing selectivity against JAK2 driven hematopoietic changes. Our program began with a conformationally constrained piperazinyl-pyrimidine Type 1 ATP site inhibitor, subsequent work led to the discovery of PF-06700841 (compound 23), which is in Phase II clinical development (NCT02969018, NCT02958865, NCT03395184, and NCT02974868).
A mild and high-yielding cyanating reaction of amine, sulfur, and carbanion nucleophiles is reported here using 1-cyanoimidazole as an electrophilic cyanating agent.
The recent discovery that small molecule ligands for the peptidyl−prolyl isomerase (PPIase) FKBP12 possess powerful neuroprotective and neuroregenerative properties in vitro and in vivo suggests ...therapeutic utility for such compounds in neurodegenerative disease. The neurotrophic effects of these compounds are independent of the immunosuppressive pathways by which drugs such as FK506 and rapamycin operate. Previous work by ourselves and other groups exploring the structure−activity relationships (SAR) of small molecules that mimic only the FKBP binding domain portion of FK506 has focused on esters of proline and pipecolic acid. We have explored amide and thioester analogues of these earlier structures and found that they too are extremely potent in promoting recovery of lesioned dopaminergic pathways in a mouse model of Parkinson's disease. Several compounds were shown to be highly effective upon oral administration after lesioning of the dopaminergic pathway, providing further evidence of the potential clinical utility of a variety of structural classes of FKBP12 ligands.
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