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1.
J Am Chem Soc ; 144(43): 19953-19972, 2022 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-36269121

RESUMEN

The total syntheses of aflastatin A and its C3-C48 degradation fragment (6a, R = H) have been accomplished. The syntheses feature several complex diastereoselective fragment couplings, including a Felkin-selective trityl-catalyzed Mukaiyama aldol reaction, a chelate-controlled aldol reaction involving soft enolization with magnesium, and an anti-Felkin-selective boron-mediated oxygenated aldol reaction. Careful comparison of the spectroscopic data for the synthetic C3-C48 degradation fragment to that reported by the isolation group revealed a structural misassignment in the lactol region of the naturally derived degradation product. Ultimately, the data reported for the naturally derived aflastatin A C3-C48 degradation lactol (6a, R = H) were attributed to its derivative lactol trideuteriomethyl ether (6c, R = CD3). Additionally, the revised absolute configurations of six stereogenic centers (C8, C9, and C28-C31) were confirmed.


Asunto(s)
Aldehídos , Pirrolidinonas , Boro , Estereoisomerismo , Estructura Molecular
2.
Am J Emerg Med ; 38(4): 741-745, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31230922

RESUMEN

BACKGROUND: The use of ABCD3-I score for Transient ischemic attack (TIA) evaluation has not been widely investigated in the ED. We aim to determine the performance and cost-effectiveness of an ABCD3-I based pathway for expedited evaluation of TIA patients in the ED. METHODS: We conducted a single-center, pre- and post-intervention study among ED patients with possible TIA. Accrual occurred for seven months before (Oct. 2016-April 2017) and after (Oct. 2017-April 2018) implementing the ABCD3-I algorithm with a five-month wash-in period (May-Sept. 2017). Total ED length of stay (LOS), admissions to the hospital, healthcare cost, and 90-day ED returns with subsequent stroke were analyzed and compared. RESULTS: Pre-implementation and post-implementation cohorts included 143 and 118 patients respectively. A total of 132 (92%) patients were admitted to the hospital in the pre-implementation cohort in comparison to 28 (24%) patients admitted in the post-implementation cohort (p < 0.001) with similar 90-day post-discharge stroke occurrence (2 in pre-implementation versus 1 in post-implementation groups, p > 0.05). The mean ABCD2 scores were 4.5 (1.4) in pre- and 4.1 (1.3) in post-implementation cohorts (p = 0.01). The mean ABCD3-I scores were 4.5 (1.8) in post-implementation cohorts. Total ED LOS was 310 min (201, 420) in pre- and 275 min (222, 342) in post-implementation cohorts (p > 0.05). Utilization of the ABCD3-I algorithm saved an average of over 40% of total healthcare cost per patient in the post-implementation cohort. CONCLUSIONS: The initiation of an ABCD3-I based pathway for TIA evaluation in the ED significantly decreased hospital admissions and cost with similar 90-day neurological outcomes.


Asunto(s)
Ataque Isquémico Transitorio/diagnóstico , Transportadoras de Casetes de Unión a ATP/análisis , Transportadoras de Casetes de Unión a ATP/sangre , Anciano , Estudios de Cohortes , Servicio de Urgencia en Hospital/organización & administración , Servicio de Urgencia en Hospital/estadística & datos numéricos , Femenino , Humanos , Ataque Isquémico Transitorio/sangre , Ataque Isquémico Transitorio/fisiopatología , Tiempo de Internación/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Medición de Riesgo/métodos , Factores de Riesgo , Accidente Cerebrovascular/prevención & control , Factores de Tiempo
3.
J Org Chem ; 82(23): 12246-12256, 2017 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-29096057

RESUMEN

We report the diastereoselective synthesis of novel spiropiperidine templates for use in SAR studies of ß-secretase (BACE) inhibitors and also as versatile ligands for other receptor types. The overall synthetic approach stems from chiral starting material benzyl (S)-2-methyl-4-oxopiperidine-1-carboxylate and employs an Overman rearrangement to control the stereochemistry at the quaternary center. This process is followed by a Grubbs metathesis to close a five-membered "top" ring to form an α,ß-unsaturated lactam or an α,ß-unsaturated sultam. We also demonstrate that this chemistry can accommodate additional substituents on the lactam/sultam ring and allows late stage sequential functionalization of the amine and amide nitrogens to rapidly produce diverse analogues.

4.
J Org Chem ; 80(16): 8417-23, 2015 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-26172089

RESUMEN

An approach to the synthesis of sulfonamides from sulfamoyl inner salts and organometallic species is presented. A range of sulfamoyl carbamates, amines, and metals are explored. Primary, secondary, and tertiary alkyl-, aryl-, and heteroaryllitihium and magnesium nucleophiles were successful. This approach yields bench-stable intermediates and avoids many of the functional group incompatibilities, regioselectivity issues, and high-energy reagents generally associated with the synthesis of sulfonamides. Additionally, the products may be purified by basic extraction or salt formation, avoiding chromatography.


Asunto(s)
Carbamatos/química , Compuestos Organometálicos/química , Sulfonamidas/síntesis química , Catálisis , Indicadores y Reactivos/química , Estructura Molecular , Sulfonamidas/química
5.
J Clin Med Res ; 10(5): 445-451, 2018 May.
Artículo en Inglés | MEDLINE | ID: mdl-29581808

RESUMEN

BACKGROUND: Emergency department (ED) shift handoffs are potential sources of delay in care. We aimed to determine the impact that using standardized reporting tool and process may have on throughput metrics for patients undergoing a transition of care at shift change. METHODS: We performed a prospective, pre- and post-intervention quality improvement study from September 1 to November 30, 2015. A handoff procedure intervention, including a mandatory workshop and personnel training on a standard reporting system template, was implemented. The primary endpoint was patient length of stay (LOS). A comparative analysis of differences between patient LOS and various handoff communication methods were assessed pre- and post-intervention. Communication methods were entered a multivariable logistic regression model independently as risk factors for patient LOS. RESULTS: The final analysis included 1,006 patients, with 327 comprising the pre-intervention and 679 comprising the post-intervention populations. Bedside rounding occurred 45% of the time without a standard reporting during pre-intervention and increased to 85% of the time with the use of a standard reporting system in the post-intervention period (P < 0.001). Provider time (provider-initiated care to patient care completed) in the pre-intervention period averaged 297 min, but decreased to 265 min in the post-intervention period (P < 0.001). After adjusting for other communication methods, the use of a standard reporting system during handoff was associated with shortened ED LOS (OR = 0.60, 95% CI 0.40 - 0.90, P < 0.05). CONCLUSIONS: Standard reporting system use during emergency physician handoffs at shift change improves ED throughput efficiency and is associated with shorter ED LOS.

6.
J Med Chem ; 60(20): 8538-8551, 2017 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-28957634

RESUMEN

As part of our effort in identifying phosphodiesterase (PDE) 4B-preferring inhibitors for the treatment of central nervous system (CNS) disorders, we sought to identify a positron emission tomography (PET) ligand to enable target occupancy measurement in vivo. Through a systematic and cost-effective PET discovery process, involving expression level (Bmax) and biodistribution determination, a PET-specific structure-activity relationship (SAR) effort, and specific binding assessment using a LC-MS/MS "cold tracer" method, we have identified 8 (PF-06445974) as a promising PET lead. Compound 8 has exquisite potency at PDE4B, good selectivity over PDE4D, excellent brain permeability, and a high level of specific binding in the "cold tracer" study. In subsequent non-human primate (NHP) PET imaging studies, [18F]8 showed rapid brain uptake and high target specificity, indicating that [18F]8 is a promising PDE4B-preferring radioligand for clinical PET imaging.


Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Inhibidores de Fosfodiesterasa/metabolismo , Tomografía de Emisión de Positrones/métodos , Animales , Corteza Cerebral/metabolismo , Cromatografía Liquida , Descubrimiento de Drogas , Macaca fascicularis , Ensayo de Unión Radioligante , Relación Estructura-Actividad , Espectrometría de Masas en Tándem
7.
ACS Comb Sci ; 17(11): 653-7, 2015 Nov 09.
Artículo en Inglés | MEDLINE | ID: mdl-26434694

RESUMEN

A sulfur-functionalized aminoacrolein derivative is used for the efficient and selective synthesis of heterocyclic sulfonyl chlorides, sulfonyl fluorides, and sulfonamides. The development of a 3-step parallel medicinal chemistry (PMC) protocol for the synthesis of pyrazole-4-sulfonamides effectively demonstrates the utility of this reagent. This reactivity was expanded to provide rapid access to other heterocyclic sulfonyl fluorides, including pyrimidines and pyridines, whose corresponding sulfonyl chlorides lack suitable chemical stability.


Asunto(s)
Compuestos Heterocíclicos/síntesis química , Ácidos Sulfínicos/síntesis química , Sulfonamidas/síntesis química , Química Farmacéutica , Técnicas Químicas Combinatorias , Compuestos Heterocíclicos/química , Estructura Molecular , Ácidos Sulfínicos/química , Sulfonamidas/química
8.
J Med Chem ; 58(6): 2678-702, 2015 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-25695670

RESUMEN

The identification of centrally efficacious ß-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) has historically been thwarted by an inability to maintain alignment of potency, brain availability, and desired absorption, distribution, metabolism, and excretion (ADME) properties. In this paper, we describe a series of truncated, fused thioamidines that are efficiently selective in garnering BACE1 activity without simultaneously inhibiting the closely related cathepsin D or negatively impacting brain penetration and ADME alignment, as exemplified by 36. Upon oral administration, these inhibitors exhibit robust brain availability and are efficacious in lowering central Amyloid ß (Aß) levels in mouse and dog. In addition, chronic treatment in aged PS1/APP mice effects a decrease in the number and size of Aß-derived plaques. Most importantly, evaluation of 36 in a 2-week exploratory toxicology study revealed no accumulation of autofluorescent material in retinal pigment epithelium or histology findings in the eye, issues observed with earlier BACE1 inhibitors.


Asunto(s)
Amidinas/química , Amidinas/uso terapéutico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Encéfalo/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Placa Amiloide/tratamiento farmacológico , Enfermedad de Alzheimer/tratamiento farmacológico , Amidinas/farmacocinética , Amidinas/farmacología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Perros , Diseño de Fármacos , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Humanos , Masculino , Ratones , Modelos Moleculares , Placa Amiloide/metabolismo , Placa Amiloide/patología , Ratas , Ratas Wistar , Compuestos de Sulfhidrilo/química , Compuestos de Sulfhidrilo/farmacocinética , Compuestos de Sulfhidrilo/farmacología , Compuestos de Sulfhidrilo/uso terapéutico
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