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ABSTRACT: We have produced a 5-year mean secular variation (SV) of the geomagnetic field for the period 2020-2025. We use the NASA Geomagnetic Ensemble Modeling System (GEMS), which consists of the NASA Goddard geodynamo model and ensemble Kalman filter (EnKF) with 400 ensemble members. Geomagnetic field models are used as observations for the assimilation, including gufm1 (1590-1960), CM4 (1961-2000) and CM6 (2001-2019). The forecast involves a bias correction scheme that assumes that the model bias changes on timescales much longer than the forecast period, so that they can be removed by successive forecast series. The algorithm was validated on the time period 2010-2015 by comparing with CM6 before being applied to the 2020-2025 time period. This forecast has been submitted as a candidate predictive model of IGRF-13 for the period 2020-2025.
RESUMO
A series of ß2-adrenoceptor agonists with an 8-(2-amino-1-hydroxyethyl)-6-hydroxy-1,4-benzoxazine-3(4H)-one moiety is presented. The stimulatory effects of the compounds on human ß2-adrenoceptor and ß1-adrenoceptor were characterized by a cell-based assay. Their smooth muscle relaxant activities were tested on isolated guinea pig trachea. Most of the compounds were found to be potent and selective agonists of the ß2-adrenoceptor. One of the compounds, (R)-18c, possessed a strong ß2-adrenoceptor agonistic effect with an EC50 value of 24â¯pM. It produced a full and potent airway smooth muscle relaxant effect same as olodaterol. Its onset of action was 3.5â¯min and its duration of action was more than 12â¯h in an in vitro guinea pig trachea model of bronchodilation. These results suggest that (R)-18c is a potential candidate for long-acting ß2-AR agonists.
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Agonistas Adrenérgicos beta/farmacologia , Benzoxazinas/farmacologia , Desenho de Fármacos , Receptores Adrenérgicos beta 2/metabolismo , Agonistas Adrenérgicos beta/síntese química , Agonistas Adrenérgicos beta/química , Animais , Benzoxazinas/síntese química , Benzoxazinas/química , Relação Dose-Resposta a Droga , Cobaias , Células HEK293 , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Traqueia/efeitos dos fármacos , Traqueia/metabolismoRESUMO
A series of novel ß2-adrenoceptor agonists with a 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one moiety was designed, synthesized and evaluated for biological activity in human embryonic kidney 293 cells and isolated guinea pig trachea. Compounds 9g and (R)-18c exhibited the most excellent ß2-adrenoceptor agonistic effects and high ß2/ß1-selectivity with EC50 values of 36â¯pM for 9g and 21â¯pM for (R)-18c. They produced potent airway smooth muscle relaxant effects with fast onset of action and long duration of action in an in vitro guinea pig trachea model of bronchodilation. These results support further development of the two compounds into drug candidates.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Broncodilatadores/farmacologia , Etanolaminas/farmacologia , Hidroxiquinolinas/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/síntese química , Agonistas de Receptores Adrenérgicos beta 2/metabolismo , Animais , Sítios de Ligação , Broncodilatadores/síntese química , Broncodilatadores/metabolismo , Desenho de Fármacos , Etanolaminas/síntese química , Etanolaminas/metabolismo , Cobaias , Células HEK293 , Humanos , Hidroxiquinolinas/síntese química , Hidroxiquinolinas/metabolismo , Masculino , Simulação de Acoplamento Molecular , Receptores Adrenérgicos beta 2/química , Receptores Adrenérgicos beta 2/metabolismo , Traqueia/efeitos dos fármacosRESUMO
Although ß2-agonists are crucial for treatment of chronic respiratory diseases, optimizing ß2-agonistic activity and selectivity remains essential for achieving favorable therapeutic outcomes. A structure-based molecular design workflow was employed to discover a novel class of ß2 agonists featuring a 5-hydroxy-4H-benzo[1,4]oxazin-3-one scaffold, which potently stimulated ß2 adrenoceptors (ß2-ARs). Screening for the ß2-agonistic activity and selectivity led to the identification of compound A19 (EC50 = 3.7 pM), which functioned as a partial ß2-agonist in HEK-293 cells containing endogenous ß2-ARs. Compound A19 exhibited significant relaxant effects, rapid onset time (Ot50 = 2.14 min), and long duration of action (>12 h) on isolated guinea pig tracheal strips, as well as advantageous pharmacokinetic characteristics in vivo, rendering A19 suitable for inhalation administration. Moreover, A19 suppressed the upregulation of inflammatory cytokines and leukocytes and improved lung function in a rat model of COPD, thereby indicating that A19 is a potential ß2 agonist candidate for further study.
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Agonistas de Receptores Adrenérgicos beta 2 , Receptores Adrenérgicos beta 2 , Humanos , Ratos , Animais , Cobaias , Células HEK293 , Agonistas de Receptores Adrenérgicos beta 2/farmacologiaRESUMO
Aiming to address the insufficient endocytosis ability of traditional albumin drug conjugates, this paper reports elegant guanidine modification to improve efficacy for the first time. A series of modified albumin drug conjugates were designed and synthesized with different structures, including guanidine (GA), biguanides (BGA) and phenyl (BA), and different quantities of modifications. Then, the endocytosis ability and in vitro/vivo potency of albumin drug conjugates were systematically studied. Finally, a preferred conjugate A4 was screened, which contained 15 BGA modifications. Conjugate A4 maintains spatial stability similar to that of the unmodified conjugate AVM and could significantly enhance endocytosis ability (p*** = 0.0009) compared with the unmodified conjugate AVM. Additionally, the in vitro potency of conjugate A4 (EC50 = 71.78 nmol in SKOV3 cells) was greatly enhanced (approximately 4 times) compared with that of the unmodified conjugate AVM (EC50 = 286.00 nmol in SKOV3 cells). The in vivo efficacy of conjugate A4 completely eliminated 50% of tumors at 33 mg/kg, which was significantly better than the efficacy of conjugate AVM at the same dose (P** = 0.0026). In addition, theranostic albumin drug conjugate A8 was designed to intuitively realize drug release and maintain antitumor activity similar to conjugate A4. In summary, the guanidine modification strategy could provide new ideas for the development of new generational albumin drug conjugates.
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Endocitose , Guanidina/química , Endocitose/efeitos dos fármacos , Albuminas/química , Humanos , Animais , Camundongos , Linhagem Celular , Feminino , Camundongos Endogâmicos BALB CRESUMO
INTRODUCTION: The ß2 adrenergic receptor (ß2AR) is a member of G protein-coupled receptors (GPCRs) that mediate the majority of cellular responses to external stimuli. The agonists can cause smooth muscle relaxation; therefore, many ß2AR agonists have been developed especially for the treatment of pulmonary disorders such as asthma and chronic obstructive pulmonary disease (COPD). Many new natural and synthetic compounds have been discovered and developed as novel ß2AR agonists over the past 5 years. AREAS COVERED: This review offers an update for the development of ß2AR agonists in the patents published from 2015 to 2020, including new natural and synthetic compounds for the treatment of asthma and COPD. In particular, the latest patents about compounds possessing both muscarinic receptor antagonist and ß2 adrenergic receptor agonist activity are reviewed. EXPERT OPINION: ß2AR agonists have been developed extensively for the treatment of asthma and COPD. In the past 5 years, novel agonists from both natural sources and synthetic methods were intensively developed. Compounds possessing both muscarinic receptor antagonist and ß2AR agonist activity represent a new trend in this area because they are possibly able to act together in a synergistic fashion, therefore, relieve the symptoms of patients through two distinct mechanisms.
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Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Desenvolvimento de Medicamentos , Antagonistas Muscarínicos/farmacologia , Animais , Asma/tratamento farmacológico , Asma/fisiopatologia , Humanos , Patentes como Assunto , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/fisiopatologiaRESUMO
ß2-Agonists that bind to plasmalemmal ß2-adrenoceptors causing cAMP accumulation are widely used as bronchodilators in chronic respiratory diseases. Here, we designed and synthesized a group of 8-hydroxyquinolin-2(1H)-one analogues and studied their ß2-agonistic activities with a cellular cAMP assay. Compounds B05 and C08 were identified as potent (EC50 < 20 pM) and selective ß2-agonists among the compounds tested. They behaved as partial ß2-agonists in non-overexpressed HEK293 cells, and possessed rapid smooth muscle relaxant actions and long duration of action in isolated guinea pig tracheal strip preparations. In summary, B05 and C08 are ß2-agonists with potential applicability in chronic respiratory diseases.