Discovery of a Potent, Selective, and Orally Bioavailable Tool Compound for Probing the Role of Lysophosphatidic Acid Type 2 Receptor Antagonists in Fibrotic Disorders.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease characterized by lung fibrosis leading to an irreversible decline of lung function. Current antifibrotic drugs on the market slow down but do not prevent the progression of the disease and are associated with tolerability issues. The involvement of lysophosphatidic acid receptor 2 (LPA2) in IPF is supported by LPA2 knockdown studies. To further validate the role of LPA2 receptors in modulating IPF and potentially other fibrotic processes, a potent and selective LPA2 receptor antagonist with a good pharmacokinetic (PK) profile is needed. Herein, we report the medicinal chemistry exploration that led to the discovery of a new class of highly potent and selective LPA2 antagonists. Among them, compound 58 exhibits excellent potency, selectivity, and oral PK profile, making it a suitable tool for probing the involvement of LPA2 receptors in IPF and other fibrotic processes.

Uma revisita ao desejo do psicanalista em O banquete de Platão, segundo o legado de Freud e Lacan / A revisit to the analyst's desire at Plato's The banquet, according to the legacy of Freud and Lacan / Una revisita al deseo del psicoanalista en El banquete de Platón, de acuerdo con el legado de Freud y Lacan

Objetivamos compreender o termo desejo do psicanalista enquanto direção ética da psicanálise. Para isso, o texto partirá de contribuições da conceituação do termo desejo em Freud como introdução ao termo desejo do psicanalista nomeado por Lacan, lugar esvaziado de intenções pessoais e de promessas de felicidade ao seu analisante. Ao longo do trabalho, serão revisitados alguns pontos essenciais da clássica obra literária O banquete de Platão de acordo com Lacan, destacando a relação de Sócrates e Alcibíades como possibilidade de contraponto da práxis psicanalítica. Em uma correlação com essa práxis, Sócrates foi colocado no lugar de objeto perdido, objeto agalmático para Alcibíades, ocupando um lugar de objeto na transferência do amor depositado por este último. Diante da sua sustentação e do desejo de não ceder ao discurso sedutor deste participante, Sócrates relança-o ao seu próprio desejo, tal como é recomendado a um psicanalista na condução de um tratamento. Finalmente, esse exemplo irá nos levar a uma reflexão quanto ao rigor ético da psicanálise como norteadora do desejo do psicanalista (AU)

We aim to understand the term psychoanalyst's desire as an ethical direction of psychoanalysis. For this, the text will start from contributions of the conceptualization of the term desire in Freud as an introduction to the term desire of the psychoanalyst named by Lacan, a place emptied of his personal intentions and promises of happiness to his analysand. Throughout the work, some essential points of the classic literary work Plato's The banquet will be revisited by Lacan, highlighting the relationship between Socrates and Alcibiades as a possibility for counterpointing psychoanalytic praxis. In a correlation with this praxis, Socrates may have been placed in the place of a lost object, an agalmatic object for Alcibiades, who occupied an object`s place in the transference and love deposited by the latter. Given the support and desire not to give in to this participant's seductive speech, Socrates relaunches it to his own desire as recommended by a psychoanalyst when conducting a treatment. Finally, this example will enlighten us for a reflection on the ethical rigor of psychoanalysis as guiding the psychoanalyst's desire (AU)

Nuestro objetivo es entender el término deseo del psicoanalista como una dirección ética del psicoanálisis. Para esto, el texto comenzará con contribuciones de la conceptualización del término deseo en Freud como una introducción al término deseo del psicoanalista nombrado por Lacan, un lugar vaciado de sus intenciones personales y promesas de felicidad para su analizante. Se explorarán algunos puntos esenciales de la obra literaria clásica El banquete de Platón por Lacan, destacando la relación entre Sócrates y Alcibíades como una posibilidad de contrapunto a la praxis psicoanalítica. En una correlación con esta praxis, Sócrates puede haber sido colocado en el lugar de objeto perdido, objeto agalmático para Alcibíades, quien ocupó un lugar de objeto en la transferencia y el amor depositado por este último. Delante su apoyo y deseo de no ceder ante el discurso seductor de este participante, Sócrates lo relanza a su propio deseo según lo recomendado por un psicoanalista cuando realiza el tratamiento. Finalmente, este ejemplo nos iluminará para reflexionar sobre el rigor ético del psicoanálisis como guía para el deseo del psicoanalista (AU)

Rational Design, Synthesis, and Preliminary Structure-Activity Relationships of α-Substituted-2-Phenylcyclopropane Carboxylic Acids as Inhibitors of Salmonella typhimurium O-Acetylserine Sulfhydrylase.

Cysteine is a building block for several biomolecules that are crucial for living organisms. The last step of cysteine biosynthesis is catalyzed by O-acetylserine sulfydrylase (OASS), a highly conserved pyridoxal 5'-phosphate (PLP)-dependent enzyme, present in different isoforms in bacteria, plants, and nematodes, but absent in mammals. Beside the biosynthesis of cysteine, OASS exerts a series of "moonlighting" activities in bacteria, such as transcriptional regulation, contact-dependent growth inhibition, swarming motility, and induction of antibiotic resistance. Therefore, the discovery of molecules capable of inhibiting OASS would be a valuable tool to unravel how this protein affects the physiology of unicellular organisms. As a continuation of our efforts toward the synthesis of OASS inhibitors, in this work we have used a combination of computational and spectroscopic approaches to rationally design, synthesize, and test a series of substituted 2-phenylcyclopropane carboxylic acids that bind to the two S. typhymurium OASS isoforms at nanomolar concentrations.

Further insights into the SAR of α-substituted cyclopropylamine derivatives as inhibitors of histone demethylase KDM1A.

Epigenetics alterations including histone methylation and acetylation, and DNA methylation, are thought to play important roles in the onset and progression of cancer in numerous tumour cell lines. Lysine-specific demethylase 1 (LSD1 or KDM1A) is highly expressed in different cancer types and inhibiting KDM1A activity seems to have high therapeutic potential in cancer treatment. In the recent years, several inhibitors of KDM1A have been prepared and disclosed. The majority of these derivatives were designed based on the structure of tranylcypromine, as the cyclopropane core is responsible for the covalent interaction between the inhibitor and the catalytic domain of KDM proteins. In this study, we have further extended the SAR regarding compounds 1a-e, which were recently found to inhibit KDM1A with good activity. The decoration of the phenyl ring at the ß-position of the cyclopropane ring with small functional groups, mostly halogenated, and in particular at the meta position, led to a significant improvement of the inhibitory activity against KDM1A, as exemplified by compound 44a, which has a potency in the low nanomolar range (31 nM).