Discovery of N-(Indazol-3-yl)piperidine-4-carboxylic Acids as RORγt Allosteric Inhibitors for Autoimmune Diseases

The clinical success of anti-IL-17 monoclonal antibodies (i.e., Cosentyx and Taltz) has validated Th17 pathway modulation for the treatment of autoimmune diseases. The nuclear hormone receptor RORγt is a master regulator of Th17 cells and affects the production of a host of cytokines, including IL-17A, IL-17F, IL-22, IL-26, and GM-CSF. Substantial interest has been spurred across both academia and industry to seek small molecules suitable for RORγt inhibition. A variety of RORγt inhibitors have been reported in the past few years, the majority of which are orthosteric binders. Here we disclose the discovery and optimization of a class of inhibitors, which bind differently to an allosteric binding pocket. Starting from a weakly active hit 1, a tool compound 14 was quickly identified that demonstrated superior potency, selectivity, and off-target profile. Further optimization focused on improving metabolic stability. Replacing the benzoic acid moiety with piperidinyl carboxylate, modifying the 4-aza-indazole core in 14 to 4-F-indazole, and incorporating a key hydroxyl group led to the discovery of 25, which possesses exquisite potency and selectivity, as well as an improved pharmacokinetic profile suitable for oral dosing.FWN – Publicaties zonder aanstelling Universiteit Leide

Água aquecida e radiação UV-C no controle pós-colheita de Cryptosporiopsis perennans em maçãs Heated water and UV-C radiation to postharvest control of Cryptosporiopsis perennans on apples

O objetivo deste trabalho foi avaliar a colonização de Cryptosporiopsis perennans na epiderme de maçãs e a eficiência da aplicação de água aquecida e radiação UV-C no controle desse patógeno. Em maçãs submetidas à inoculação de C. perennans, a colonização de lenticelas e das áreas adjacentes pelo patógeno foi avaliada por microscopia eletrônica de varredura. A sensibilidade dos conídios de C. perennans aos tratamentos foi avaliada em suspensão aquosa, às temperaturas de 28, 45, 50 e 55ºC, por 15 e 30 s, e às doses de radiação UV-C de 0,018, 0,037, 0,075, 0,150, 0,375, 0,750, 1,500 e 3,000 kJ m-2. Em maçãs submetidas à inoculação de C. perennans, foram avaliados os efeitos de 0,375, 0,750 e 1,500 kJ m-2 de radiação UV-C e da aspersão de água aquecida à 50ºC, por 15 e 30 s no controle do patógeno. O fungo produziu abundante micélio e conídios nas lenticelas e nas áreas adjacentes, na epiderme das maçãs. A água aquecida a 50ºC por 15 s e à dose de radiação de UV-C de 0,750 kJ m-2 reduzem em mais de 99% a sobrevivência de conídios. A aspersão de água aquecida a 50ºC por 15 s e à dose de radiação de UV-C de 0,375 kJ m-2, controlam C. perennans em maçãs.<br>The objective of this work was to assess the colonization of Cryptosporiopsis perennans in the epidermis of apples and the efficiency of heated water and UV-C radiation application to control this pathogen. In apples inoculated with C. perennans, the colonization of lenticels and adjacent areas by the pathogen was observed by electronic scanning microscopy. The sensitivity of C. perennans conidia was evaluated in aqueous suspension, at temperatures of 28, 45, 50 and 55ºC for 15 and 30 s, and at UV-C radiation doses of 0.018, 0.037, 0.075, 0.150, 0.375, 0.750, 1.500 and 3.000 kJ m-2. The effects of UV-C radiation doses at 0.375, 0.750 and 1.500 kJ m-2 and heated water at 50ºC, sprayed during 15 and 30 s were evaluated for controlling C. perennans in apples inoculated with the pathogen. The fungus produced abundant mycelium and conidia in lenticels and adjacent areas on the epidermis of the apples. The heated water at 50ºC during 15 s and a 0.750 kJ m-2 UV-C radiation dose reduced conidia survival in more than 99%. Heated water sprayed at 50ºC during 15 s and a UV-C radiation dose of 0.375 kJ m-2 control C. perennans in apples