RESUMEN
As we celebrate International Women's Day 2024 with the theme "Inspire Inclusion", the women of the ACS Medicinal Chemistry Division (MEDI) want to foster a sense of belonging, relevance, and empowerment by sharing uplifting stories of what inspired them to become medicinal chemists. In this editorial, we are featuring female medicinal chemistry scientists to provide role models, encouragement, and inspiration to others. We asked women medicinal chemists to contribute a brief paragraph about what inspired them to become medicinal chemists or what inspires them today as medicinal chemists. The responses and contributions highlight their passions and motivations, such as their love of the sciences and their drive to improve human health by contributing to basic research and creating lifesaving drugs.
RESUMEN
As we celebrate International Women's Day 2024 with the theme "Inspire Inclusion", the women of the ACS Medicinal Chemistry Division (MEDI) want to foster a sense of belonging, relevance, and empowerment by sharing uplifting stories of what inspired them to become medicinal chemists. In this editorial, we are featuring female medicinal chemistry scientists to provide role models, encouragement, and inspiration to others. We asked women medicinal chemists to contribute a brief paragraph about what inspired them to become medicinal chemists or what inspires them today as medicinal chemists. The responses and contributions highlight their passions and motivations, such as their love of the sciences and their drive to improve human health by contributing to basic research and creating lifesaving drugs.
Asunto(s)
Química Farmacéutica , Poder Psicológico , Humanos , FemeninoRESUMEN
The kappa agonist structure-activity relationship around the novel, pyrrolidinyl substituted pyranopiperazine scaffold was developed. More specifically, the dichloroPhenylAcetamide-Pyrrolidinyl-PyranoPiperazine (PAPPP) core A was the focus of our work. The modulation of kappa receptor potency/G-protein activation and arrestin recruitment with respect to changes of the piperazine R group in A was demonstrated. Reduced ß2-arrestin recruitment and differential G-protein bias were observed for select analogues. To better understand the subtlety in receptor signaling, analogues were profiled as the resolved enantiomers. To determine in vivo target engagement, a subset of compounds was tested in mice for stimulation of serum prolactin, a neuroendocrine biomarker of KOR-agonist effects. Additional in vivo characterization included measurement of potential unwanted effects of kappa receptor activation such as sedation. These studies demonstrate a novel kappa receptor agonist scaffold with potential for G-protein signaling bias to probe in vivo pharmacology.
Asunto(s)
Analgésicos Opioides , Receptores Opioides kappa , Analgésicos Opioides/farmacología , Animales , Arrestinas/metabolismo , Proteínas de Unión al GTP/metabolismo , Ratones , Receptores Opioides kappa/metabolismo , Transducción de SeñalRESUMEN
In a recent disclosure, we described the discovery of dimeric, prolinamide-based NS5A replication complex inhibitors exhibiting excellent potency towards an HCV genotype 1b replicon. That disclosure dealt with the SAR exploration of the peripheral region of our lead chemotype, and herein is described the SAR uncovered from a complementary effort that focused on the central core region. From this effort, the contribution of the core region to the overall topology of the pharmacophore, primarily vector orientation and planarity, was determined, with a set of analogs exhibiting <10 nM EC(50) in a genotype 1b replicon assay.
Asunto(s)
Antivirales/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/farmacología , Carbamatos , Hepacivirus/efectos de los fármacos , Imidazoles/química , Imidazoles/farmacología , Concentración 50 Inhibidora , Estructura Molecular , Prolina/análogos & derivados , Prolina/química , Prolina/farmacología , Pirrolidinas , Relación Estructura-Actividad , Valina/análogos & derivados , Proteínas no Estructurales Virales/química , Replicación Viral/efectos de los fármacosRESUMEN
Isonitriles and ureas undergo a condensation reaction in the presence of acid chlorides to give formamidine ureas, for which no general synthetic routes currently exist. A mechanism is proposed in which the key intermediate is an electrophilic adduct of isonitrile and acid chloride. The process is tolerant of moderate variability in the nature of the components, and access to formamidine ureas of varying substitution patterns is further enhanced by a facile exchange reaction with amines. [reaction: see text]
