Design, Synthesis, and Evaluation of a Novel Series of Indole Sulfonamide Peroxisome Proliferator Activated Receptor (PPAR) α/γ/δ Triple Activators: Discovery of Lanifibranor, a New Antifibrotic Clinical Candidate.

Here, we describe the identification and synthesis of novel indole sulfonamide derivatives that activate the three peroxisome proliferator activated receptor (PPAR) isoforms. Starting with a PPARα activator, compound 4, identified during a high throughput screening (HTS) of our proprietary screening library, a systematic optimization led to the discovery of lanifibranor (IVA337) 5, a moderately potent and well balanced pan PPAR agonist with an excellent safety profile. In vitro and in vivo, compound 5 demonstrated strong activity in models that are relevant to nonalcoholic steatohepatitis (NASH) pathophysiology suggesting therapeutic potential for NASH patients.

Bioethics and law: from the abundance of sources to the confusion of genders.

The law of bioethics reveals frequent confusion in the definition and role devolved to the law and ethics. The purpose of this paper is to illustrate some of these confusions.

Structure activity relationships of new inhibitors of mammalian 2,3-oxidosqualene cyclase designed from isoquinoline derivatives.

We have designed more potent inhibitors from the previously reported LF 05-0038, a 6-isoquinolinol based inhibitor of 2,3-oxidosqualene cyclase (IC50: 1.1 microM). Replacement of the 3-OH group by various 3-substituted amino groups, and modification of the alkyl chain borne by the endocyclic nitrogen led to inhibitors with IC50 in the range of 0.15 to 1 microM. In a second step, opening of the bicyclic ring system afforded the corresponding aminoalkylpiperidines which were slightly more potent. Finally, introduction of suitable aromatic containing moieties on the piperidine nitrogen yielded very potent inhibitors such as 20x (IC50 = 18 nM) easy to synthesize and achiral. The recent availability of the crystal structure of squalene-hopene cyclase allowed us to construct a three-dimensional (3D) model of the related 2,3-oxidosqualene cyclase (OSC) which was tentatively used to describe the possible mode of binding of our compounds and which can be useful for designing new inhibitors.

Dehiscencia recidivante de la línea de sutura de prótesis valvulares aórticas. Tratamiento por implantación de tubo valvulado en posición supracoronaria / Repeated -stitch failure of the suture line of aortic valve replacement. The use of supracoronary

En este trabajo presentamos la casuística de los últimos 7 años, de las operaciones de dehiscencia recidivante de la línea de sutura de prótesis valvulares aórticas, tratadas mediante la implantación de un tubo valvulado en posición supracoronaria, utilizando una variante de la técnica descrita por Danielson y otros autores. Hacemos una descripción de la operación para la cual utilizamos un tubo de precoagulado o de baja porosidad del mismo diámetro que la aorta ascendente, dentro del cual se implanta una prótesis de disco. El tubo de sutura por encima de los ostium coronarios, previo cierre de los mismos con sutura directa. Distalmente, el tubo se sutura a la aorta ascendente en forma termino-terminal y luego se colocan los hemoductos a la coronaria derecha y al tronco de la izquierda. Esta variante técnica nos permitió suprimir las posibilidades de nuevas dehiscencias, asegurando además una mejor perfusión al territorio de la coronaria izquierda y prácticamente eliminar la posibilidad de residiva de la infección a nivel del anillo fibroso y de las cavidades residuales de los aneurismas micóticos y abscesos. Presentamos además el estudio de nuestra casuística y el análisis de los resultados de 8 pacientes intervenidos, con 5 sobrevivencias a mediano y largo plazo