Soluble epoxide hydrolase inhibitors: design, synthesis, in vitro profiling and in vivo evaluation in murine models of pain

Trabajo presentado en el ASPET Annual Meeting at Experimental Biology 2022, celebrado en Philadelphia, PA (Estados Unidos), del 2 al 5 de abril de 2022This research by the Grant PID2020-118127RB-I00 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe” to S.V. Financial support from Fundació Bosch i Gimpera, Universitat de Barcelona (F2I grant), to S.V., and from the Xunta de Galicia (ED431G 2019/02 and ED431C 2018/21) to M.I.L. are acknowledged. Partial support was provided by NIH-NIEHS River Award R35 ES03443, NIH-NIEHS Superfund Program P42 ES004699, NINDS R01 DK107767, and NIDDK R01 DK103616 to B.D.H. S.C. acknowledges a PhD fellowship from the Universitat de Barcelona (APIF grant)

Synthesis, in Vitro Profiling, and in Vivo Evaluation of Benzohomoadamantane-Based Ureas for Visceral Pain: A New Indication for Soluble Epoxide Hydrolase Inhibitors

The soluble epoxide hydrolase (sEH) has been suggested as a pharmacological target for the treatment of several diseases, including pain-related disorders. Herein, we report further medicinal chemistry around new benzohomoadamantane-based sEH inhibitors (sEHI) in order to improve the drug metabolism and pharmacokinetics properties of a previous hit. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies, two candidates were evaluated in vivo in a murine model of capsaicin-induced allodynia. The two compounds showed an anti-allodynic effect in a dose-dependent manner. Moreover, the most potent compound presented robust analgesic efficacy in the cyclophosphamide-induced murine model of cystitis, a well-established model of visceral pain. Overall, these results suggest painful bladder syndrome as a new possible indication for sEHI, opening a new range of applications for them in the visceral pain field

Synthetic approaches towards organic products of pharmaceutical interest

[eng] The present thesis focuses on the study and synthesis of three active principles (APIs) with therapeutic activity. Although these compounds are commercially available, their route of synthesis are very old, therefore it is required process optimization and preferably, innovation whenever possible. The work will be divided into three chapters: the first part is based on the synthesis and optimization of an antipsychotic agent, while the second and third blocks are related to the preparation and optimization of two antihypertensive drugs. Taking into account that many procedures described in the literature for obtaining these compounds lack reproducibility or provide insufficient information, it is necessary to investigate and improve reaction conditions. For this purpose, it is mandatory to detect the most critical points that alter the process synthesis. Process development and optimization involves the adoption of criteria such as the use of non- toxic reagents and solvents, detection of occupational hazards, increase of process efficiency in terms of throughput and costs, reduction of reaction time, improvement of product quality, operational simplicity among other examples. As soon as the best reaction conditions are established, these experiments are replicated to study the feasibility of the procedure. Upon good results obtaining, the process rate is increased in the laboratory; as a way for assessing continuous evaluation for the most transcendental aspects. Some of the parameters that can be altered during the scale-up process are the following ones: lower conversion of starting reagents to final product, appearance or intensification of impurities, risk of temperature rise, etc. Once the methodology for synthesizing these compounds is consolidated to quantify process robustness, the process information can be protected through a patent application. However, the main goal of this thesis is to design an optimal process for manufacturing these compounds at industrial-scale production meeting GMP requirements.[cat] La present tesi se centra en l’estudi i la síntesi de tres principis actius (API, segons les sigles en anglès) amb activitat terapèutica. Tot i que aquests compostos són disponibles comercialment, les seves rutes de síntesi són molt antigues i per tant, requereixen un procés d’optimització i innovació sempre que sigui possible. El treball es dividirà en dos blocs en funció de la diana terapèutica: la primera part se centra en la síntesi i optimització d’un agent antipsicòtic, mentre que la segona part es basa en la preparació i optimització de fàrmacs antihipertensius. Pel que fa aquest darrer capítol, es presenta l’estudi i síntesi de dos APIs que formen part de la mateixa família de compostos. Tenint en compte que molts dels processos de obtenció d’aquests compostos descrits en la bibliografia manquen de reproductibilitat o que aporten poca informació, és necessari investigar i millorar les condicions de reacció. Amb aquesta finalitat, és imprescindible la detecció dels punts més crítics que afecten al procés de síntesi. La optimització del desenvolupament de les rutes de síntesi implica abordar una sèrie de criteris com per exemple l’ús de reactius i dissolvents no tòxics, detecció de riscos laborals, increment d’eficàcia de procés en termes de rendiment i costos, reducció del temps de reacció, increment de la qualitat de producte, aplicació d’operacions més senzilles entre altres exemples. Tan bon punt com s’estableixen les millors condicions de reacció, es procedeix amb la replicació d’aquests experiments per estudiar la viabilitat del procediment. La obtenció de bons resultats dóna pas a l’escalat de procés a nivell de laboratori; d’aquesta manera se segueix amb l’avaluació continua dels aspectes més transcendentals. Els paràmetres que poden ser alterats durant l’escalat de procés poden ser molt variats: conversió més lenta dels reactius de partida a producte final, aparició o intensificació d’impureses, risc d’increment de temperatura etc. Una vegada es consolida la metodologia per a sintetitzar aquests compostos i es comprova la robustesa del procés, es valora la possibilitat de protegir la informació de procés mitjançant una sol·licitud de patent. Tanmateix, l’objectiu general de la present tesi radica en dissenyar un procés òptim per a la fabricació d’aquests compostos a nivell industrial complint requeriments GMP

Synthesis, In Vitro Profiling, and In Vivo Evaluation of Benzohomoadamantane-Based Ureas for Visceral Pain: A New Indication for Soluble Epoxide Hydrolase Inhibitors

The soluble epoxide hydrolase (sEH) has been suggested as a pharmacological target for the treatment of several diseases, including pain-related disorders. Herein, we report further medicinal chemistry around new benzohomoadamantane-based sEH inhibitors (sEHI) in order to improve the drug metabolism and pharmacokinetics properties of a previous hit. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies, two candidates were evaluated in vivo in a murine model of capsaicin-induced allodynia. The two compounds showed an anti-allodynic effect in a dose-dependent manner. Moreover, the most potent compound presented robust analgesic efficacy in the cyclophosphamide-induced murine model of cystitis, a well-established model of visceral pain. Overall, these results suggest painful bladder syndrome as a new possible indication for sEHI, opening a new range of applications for them in the visceral pain field