From the Design to the In Vivo Evaluation of Benzohomoadamantane-Derived Soluble Epoxide Hydrolase Inhibitors for the Treatment of Acute Pancreatitis.

The pharmacological inhibition of soluble epoxide hydrolase (sEH) is efficient for the treatment of inflammatory and pain-related diseases. Numerous potent sEH inhibitors (sEHIs) present adamantyl or phenyl moieties, such as the clinical candidates AR9281 or EC5026. Herein, in a new series of sEHIs, these hydrophobic moieties have been merged in a benzohomoadamantane scaffold. Most of the new sEHIs have excellent inhibitory activities against sEH. Molecular dynamics simulations suggested that the addition of an aromatic ring into the adamantane scaffold produced conformational rearrangements in the enzyme to stabilize the aromatic ring of the benzohomoadamantane core. A screening cascade permitted us to select a candidate for an in vivo efficacy study in a murine model of cerulein-induced acute pancreatitis. The administration of 22 improved the health status of the animals and reduced pancreatic damage, demonstrating that the benzohomoadamantane unit is a promising scaffold for the design of novel sEHIs.

The medication discrepancy detection service: A cost-effective multidisciplinary clinical approach / Servicio de detección de discrepancias de la medicación: un estudio multidisciplinar y coste-efectivo

OBJECTIVE: To estimate the effectiveness of a Medication Discrepancy Detection Service (MDDS), a collaborative service between the community pharmacy and Primary Care. DESIGN: Non-controlled before-and-after study. SETTING: Bidasoa Integrated Healthcare Organisation, Gipuzkoa, Spain. PARTICIPANTS: The service was provided by a multidisciplinary group of community pharmacists (CPs), general practitioners (GPs), and primary care pharmacists, to patients with discrepancies between their active medical charts and medicines that they were actually taking. Outcomes: The primary outcomes were the number of medicines, the type of discrepancy, and GPs' decisions. Secondary outcomes were time spent by CPs, emergency department (ED) visits, hospital admissions, and costs. RESULTS: The MDDS was provided to 143 patients, and GPs resolved discrepancies for 126 patients. CPs identified 259 discrepancies, among which the main one was patients not taking medicines listed on their active medical charts (66.7%, n = 152). The main GPs' decision was to withdraw the treatment (54.8%, n = 125), which meant that the number of medicines per patient was reduced by 0.92 (9.12 ± 3.82 vs. 8.20 ± 3.81; p < .0001). The number of ED visits and hospital admissions per patient were reduced by 0.10 (0.61 ± .13 vs 0.52 ± 0.91; p = .405 and 0.17 (0.33 ± 0.66 vs. 0.16 ± 0.42; p = .007), respectively. The cost per patient was reduced by (Euro)444.9 ((Euro)1003.3 ± 2165.3 vs. (Euro)558.4 ± 1273.0; p = .018). CONCLUSION: The MDDS resulted in a reduction in the number of medicines per patients and number of hospital admissions, and the service was associated with affordable, cost-effective ratios

OBJETIVOS: Estimar la efectividad del servicio de detección de discrepancias de la medicación, un servicio de colaboración entre la farmacia comunitaria y la atención primaria. DISEÑO: Estudio de intervención antes-después, sin grupo control. Emplazamiento: Organización Sanitaria Integrada de Bidasoa, Gipuzkoa, España. PARTICIPANTES: El servicio fue ofrecido por un grupo multidisciplinar que incluía farmacéuticos comunitarios (FC), médicos de atención primaria (MAP) y farmacéuticos de atención primaria a pacientes que presentaban discrepancias entre la medicación prescrita en la hoja de tratamiento activo y lo que realmente estaban tomando. Mediciones principales: Las variables principales del estudio fueron el número de medicamentos, tipo de discrepancia y la decisión del MAP. Las variables secundarias fueron tiempo invertido por el farmacéutico, visitas al servicio de urgencias, ingresos hospitalarios y los costes. RESULTADOS: El servicio se ofreció a 143 pacientes, y el MAP resolvió las discrepancias de un total de 126 pacientes. El FC identificó 259 discrepancias de las cuales la mayoría fue que el paciente no estaba tomando un medicamento prescrito (66,7%, n = 152). En la mayoría de los casos, la decisión del MAP fue suspender el tratamiento (54,8%, n = 125); el número de medicamentos que tomaba el paciente se redujo en un 0,92 (9,12 ± 3,82 vs. 8,20 ± 3,81; p < 0,0001). El número de visitas al hospital y los ingresos hospitalarios se redujeron en 0,10 (0,61 ± 0,13 vs. 0,52 ± 0,91; p = 0,405) y 0,17 puntos (0,33 ± 0,66 vs. 0,16 ± 0,42; p = 0,007), respectivamente. El coste por paciente se redujo en 444,9 (Euro) (1.003,3 ± 2.165,3 vs. 558,4 (Euro) ± 1.273,0; p = 0,018). CONCLUSIÓN: El servicio redujo el número de medicamentos que tomaba el paciente e ingresos hospitalarios y esto se relacionó con unos ratios de coste-efectividad positivos

The medication discrepancy detection service: A cost-effective multidisciplinary clinical approach.

OBJECTIVE: To estimate the effectiveness of a Medication Discrepancy Detection Service (MDDS), a collaborative service between the community pharmacy and Primary Care. DESIGN: Non-controlled before-and-after study. SETTING: Bidasoa Integrated Healthcare Organisation, Gipuzkoa, Spain. PARTICIPANTS: The service was provided by a multidisciplinary group of community pharmacists (CPs), general practitioners (GPs), and primary care pharmacists, to patients with discrepancies between their active medical charts and medicines that they were actually taking. OUTCOMES: The primary outcomes were the number of medicines, the type of discrepancy, and GPs' decisions. Secondary outcomes were time spent by CPs, emergency department (ED) visits, hospital admissions, and costs. RESULTS: The MDDS was provided to 143 patients, and GPs resolved discrepancies for 126 patients. CPs identified 259 discrepancies, among which the main one was patients not taking medicines listed on their active medical charts (66.7%, n=152). The main GPs' decision was to withdraw the treatment (54.8%, n=125), which meant that the number of medicines per patient was reduced by 0.92 (9.12±3.82 vs. 8.20±3.81; p<.0001). The number of ED visits and hospital admissions per patient were reduced by 0.10 (0.61±.13 vs 0.52±0.91; p=.405 and 0.17 (0.33±0.66 vs. 0.16±0.42; p=.007), respectively. The cost per patient was reduced by €444.9 (€1003.3±2165.3 vs. €558.4±1273.0; p=.018). CONCLUSION: The MDDS resulted in a reduction in the number of medicines per patients and number of hospital admissions, and the service was associated with affordable, cost-effective ratios.

2-Oxaadamant-1-yl Ureas as Soluble Epoxide Hydrolase Inhibitors: In Vivo Evaluation in a Murine Model of Acute Pancreatitis.

In vivo pharmacological inhibition of soluble epoxide hydrolase (sEH) reduces inflammatory diseases, including acute pancreatitis (AP). Adamantyl ureas are very potent sEH inhibitors, but the lipophilicity and metabolism of the adamantane group compromise their overall usefulness. Herein, we report that the replacement of a methylene unit of the adamantane group by an oxygen atom increases the solubility, permeability, and stability of three series of urea-based sEH inhibitors. Most of these oxa-analogues are nanomolar inhibitors of both the human and murine sEH. Molecular dynamics simulations rationalize the molecular basis for their activity and suggest that the presence of the oxygen atom on the adamantane scaffold results in active site rearrangements to establish a weak hydrogen bond. The 2-oxaadamantane 22, which has a good solubility, microsomal stability, and selectivity for sEH, was selected for further in vitro and in vivo studies in models of cerulein-induced AP. Both in prophylactic and treatment studies, 22 diminished the overexpression of inflammatory and endoplasmic reticulum stress markers induced by cerulein and reduced the pancreatic damage.

Exploring the size of the lipophilic unit of the soluble epoxide hydrolase inhibitors.

Soluble epoxide hydrolase (sEH) inhibitors are potential drugs for several diseases. Adamantyl ureas are excellent sEH inhibitors but have limited metabolic stability. Herein, we report the effect of replacing the adamantane group by alternative polycyclic hydrocarbons on sEH inhibition, solubility, permeability and metabolic stability. Compounds bearing smaller or larger polycyclic hydrocarbons than adamantane yielded all good inhibition potency of the human sEH (0.4 ≤ IC50 ≤ 21.7 nM), indicating that sEH is able to accommodate inhibitors of very different size. Human liver microsomal stability of diamantane containing inhibitors is lower than that of their corresponding adamantane counterparts.

Metal-free alkene oxy- and amino-perfluoroalkylations via carbocation formation by using perfluoro acid anhydrides: unique reactivity between styrenes and perfluoro diacyl peroxides.

We present a strategy for metal-free, alkene difunctionalization-type, oxy- and amino-perfluoroalkylations, using perfluoro acid anhydrides as practical and user-friendly perfluoroalkyl sources. This method provides efficient access to oxy-perfluoroalkylation products via carbocation formation due to the unique reactivity between styrenes and bis(perfluoroacyl) peroxides generated in situ from perfluoro acid anhydrides. This reaction is also applicable to metal-free intramolecular amino-perfluoroalkylation of styrenes bearing a pendant amino group. Synthetic utility of the oxy-trifluoromethylation products was confirmed by demonstrating derivatization via hydrolysis, elimination, and acid-catalyzed substitution with carbon nucleophiles. The mechanism of the carbocation formation was investigated experimentally and theoretically.

N-Heterocycle-Forming Amino/Carboperfluoroalkylations of Aminoalkenes by Using Perfluoro Acid Anhydrides: Mechanistic Studies and Applications Directed Toward Perfluoroalkylated Compound Libraries.

This work describes a practical and efficient method for synthesizing a diverse array of perfluoroalkylated amines, including N-heterocycles, to afford perfluoroalkylated chemical libraries as potential sources of drug candidates, agrochemicals, and probe molecules for chemical-biology research. Perfluoro acid anhydrides, which are commonly used in organic synthesis, were employed as a perfluoroalkyl source for intramolecular amino- and carbo-perfluoroalkylations of aminoalkenes, affording perfluoroalkylated N-heterocycles, including: aziridines, pyrrolidines, benzothiazinane dioxides, indolines, and hydroisoquinolinones. Diacyl peroxides were generated in situ from the perfluoro acid anhydrides with urea·H2O2, and allowed to react with aminoalkenes in the presence of copper catalyst to control the product selectivity between amino- and carbo-perfluoroalkylations. To illustrate the synthetic utility of bench-stable trifluoromethylated aziridine, which was prepared on a gram scale, we used it to synthesize a wide variety of trifluoromethylated amines including complex molecules, such as trifluoromethylated tetrahydroharmine and spiroindolone. A mechanistic study of the role of the copper catalyst in the aminotrifluoromethylation of allylamine suggested that Cu(I) accelerates CF3 radical formation via decomposition of diacyl peroxide, which appears to be the turnover-limiting step, while Cu(II) controls the product selectivity.

Design, synthesis and in vivo study of novel pyrrolidine-based 11ß-HSD1 inhibitors for age-related cognitive dysfunction.

Recent findings suggest that treatment with 11ß-HSD1 inhibitors provides a novel approach to deal with age-related cognitive dysfunctions, including Alzheimer's disease. In this work we report potent 11ß-HSD1 inhibitors featuring unexplored pyrrolidine-based polycyclic substituents. A selected candidate administered to 12-month-old SAMP8 mice for four weeks prevented memory deficits and displayed a neuroprotective action. This is the first time that 11ß-HSD1 inhibitors have been studied in this broadly-used mouse model of accelerated senescence and late-onset Alzheimer's disease.

Escape from adamantane: Scaffold optimization of novel P2X7 antagonists featuring complex polycycles.

The adamantane scaffold, despite being widely used in medicinal chemistry, is not devoid of problems. In recent years we have developed new polycyclic scaffolds as surrogates of the adamantane group with encouraging results in multiple targets. As an adamantane scaffold is a common structural feature in several P2X7 receptor antagonists, herein we report the synthesis and pharmacological evaluation of multiple replacement options of adamantane that maintain a good activity profile. Molecular modeling studies support the binding of the compounds to a site close to the central pore, rather than to the ATP-binding site and shed light on the structural requirements for novel P2X7 antagonists.

Searching for novel applications of the benzohomoadamantane scaffold in medicinal chemistry: Synthesis of novel 11ß-HSD1 inhibitors.

The structural and physicochemical properties of the adamantane nucleus account for its use as a chemical scaffold in multiple drugs. In the last years, we have developed new polycyclic scaffolds as surrogates of the adamantane group with encouraging results in multiple targets. As adamantane is a common structural feature in several 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitors, we have explored the ability of the 6,7,8,9,10,11-hexahydro-5H-5,9:7,11-dimethanobenzo[9]annulen-7-yl scaffold to act as a surrogate of the adamantane nucleus in a novel series of 11ß-HSD1 inhibitors. Of note, within this family of compounds one derivative is endowed with submicromolar 11ß-HSD1 inhibitory activity. Molecular modeling studies support the binding of the compounds to the active site of the enzyme. However, a fine tuning of the hydrophobicity of the size-expanded nucleus may be beneficial for the inhibitory potency.

Speciation control during Suzuki-Miyaura cross-coupling of haloaryl and haloalkenyl MIDA boronic esters.

Boronic acid solution speciation can be controlled during the Suzuki-Miyaura cross-coupling of haloaryl N-methyliminodiacetic acid (MIDA) boronic esters to enable the formal homologation of boronic acid derivatives. The reaction is contingent upon control of the basic biphase and is thermodynamically driven: temperature control provides highly chemoselective access to either BMIDA adducts at room temperature or boronic acid pinacol ester (BPin) products at elevated temperature. Control experiments and solubility analyses have provided some insight into the mechanistic operation of the formal homologation process.

Antibacterial activity of novel benzopolycyclic amines.

Staphylococcus aureus, especially strains resistant to multiple antibiotics, is a major pathogen for humans and animals. In this paper we have synthesized and evaluated the antibacterial activity of a new series of benzopolycyclic amines. Some of them exhibited µM MIC values against Staphylococcus aureus and other bacteria, including methicillin-resistant S. aureus MRSA. Compound 8 that displayed a good selectivity index, showed to be active in eliminating bacterial cells forming a preexisting biofilm.

Novel benzopolycyclic amines with NMDA receptor antagonist activity.

A new series of benzopolycyclic amines active as NMDA receptor antagonists were synthesized. Most of them exhibited increased activity compared with related analogues previously published. All the tested compounds were more potent than clinically approved amantadine and one of them displayed a lower IC50 value than memantine, an anti-Alzheimer's approved drug.

Synthesis and antiviral evaluation of bisnoradamantane sulfites and related compounds.

The reaction of a series of 1,2-diols with thionyl chloride led to bisnoradamantane sulfites in very good yields. The reaction has also been applied to related polycyclic scaffolds. The compounds have been tested for antiviral activity but none of them showed to be active. Several attempts to generate and trap SO from these polycyclic sulfites have been unsuccessful.

New oxapolycyclic cage amines with NMDA receptor antagonist and trypanocidal activities.

The synthesis of several (1,2,3,5,6,7-hexahydro-1,5:3,7-dimethano-4-benzoxonin-3-yl)amines and related compounds is reported. Several of them display very similar activity to memantine as NMDA receptor antagonists. Several derivatives showed a significant level of trypanocidal activity.