Development Automobile Engine Hood Latch

V diplomové práci se zabývá konstrukčním návrhem automobilového zámku, který má hlavní komponenty v „plastovém“ provedení (rohatka, západka, tělesa). Tyto plastové díly jsem vhodně navrhl a optimalizoval na požadované zatížení. Zároveň srovnávám plastový zámek a ocelový zámek přední kapoty, srovnávám jak cenu zámků, tak hmotnost a zatížení zámků. V krátkosti porovnávám automobilové zámky přední kapoty v současném automobilovém průmyslu. Také se zabývám etapou výroby prototypového vzorku v současnosti.The diploma thesis deals with the design of the car lock, which main components such as claw, pawl and housing are made of plastic. My main goal was to optimized these plastic parts for a certain amount of power. The following part shows a comparison of plastic lock and the steel lock of front bonnet. The following part shows a comparison of the plastic lock and the steel lock of the front bonnet. The comparison is made in terms of the price, weight and load of the locks. The diploma thesis also briefly deals with the comparison of car locks of car locks of front bonnets in the current automotive industry and the stage of prototype sample production nowadays.340 - Katedra výrobních strojů a konstruovánívelmi dobř

Discovery of Clinical Candidate <i>N</i>‑((1<i>S</i>)‑1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3‑<i>b</i>]pyrazine-4(1<i>H</i>)‑carboxamide (TAK-915): A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor for the Treatment of Cognitive Disorders

Phosphodiesterase (PDE) 2A inhibitors have emerged as a novel mechanism with potential therapeutic option to ameliorate cognitive dysfunction in schizophrenia or Alzheimer’s disease through upregulation of cyclic nucleotides in the brain and thereby achieve potentiation of cyclic nucleotide signaling pathways. This article details the expedited optimization of our recently disclosed pyrazolo­[1,5-<i>a</i>]­pyrimidine lead compound <b>4b</b>, leading to the discovery of clinical candidate <b>36</b> (TAK-915), which demonstrates an appropriate combination of potency, PDE selectivity, and favorable pharmacokinetic (PK) properties, including brain penetration. Successful identification of <b>36</b> was realized through application of structure-based drug design (SBDD) to further improve potency and PDE selectivity, coupled with prospective design focused on physicochemical properties to deliver brain penetration. Oral administration of <b>36</b> demonstrated significant elevation of 3′,5′-cyclic guanosine monophosphate (cGMP) levels in mouse brains and improved cognitive performance in a novel object recognition task in rats. Consequently, compound <b>36</b> was advanced into human clinical trials