RESUMO
Companies are increasingly relying on emission reductions attributable to their adoption of renewable electricity to achieve net-zero emission targets. However, there is a risk of double counting of emission reductions threatening the credibility of corporate climate actions due to defective accounting rules of GHG emissions related to electricity consumption and the overlap between different market-based instruments, including carbon credit markets, renewable power purchase agreements, and renewable energy certificates. Using data of 63 major Chinese companies in seven sectors, we quantitatively assess the risks of double counting related to corporate sourcing of renewables and their consequent influences on the alignment of corporate emission trajectories with the 1.5 °C goal of the Paris Agreement. Results show that 7.1% of the electricity consumed by sample companies in 2021 was from renewable energy procurement and deployment, with which they reported 8.27 Mt of CO2e emission reductions compared to the scenario with no renewable electricity consumption. However, emission reductions that could be double counted are predicted to be 0.9-1.3 times as many as emission reductions that companies will report during 2021-2030. After adjustment of the reported emissions that might be underestimated due to double counting, the overall emission trajectories of sample companies are no longer aligned with the 1.5 °C goal. Our findings suggest that it is urgently needed to improve the corporate carbon accounting rules and increase the transparency of corporate carbon disclosures.
Assuntos
Gases de Efeito Estufa , Eletricidade , Energia RenovávelRESUMO
An emission trading system (ETS) has been consistently recognized as a promising instrument to stem massive carbon emissions from energy-intensive industries. However, it remains ambiguous whether the ETS can achieve emission mitigation without undermining economic activity in specific industries in emerging running markets. This study focuses on the impact of China's four independent ETS pilots on carbon emissions, industrial competitiveness, and spatial spillover effects in the iron and steel industry. With a synthetic control method for causal inference, we find that the achievement of emission reductions was generally accompanied by losses of competitiveness in the pilot regions. An exception to this trend was seen in the Guangdong pilot, where the aggregate emissions increased due to the incentivized output created by a specific benchmarking allocation approach. Despite impaired competitiveness, the ETS did not cause significant spatial spillovers, which alleviates concerns about potential carbon leakage under unilateral climate regulation. Our findings could enlighten subsequent sector-specific assessments of the effectiveness of ETSs and are also valuable to policymakers in and outside China now considering ETSs.
Assuntos
Gases de Efeito Estufa , Ferro , Indústrias , China , Carbono/análise , Desenvolvimento Econômico , Dióxido de Carbono/análiseRESUMO
China's economic development has entered a "new normal" stage where economic growth has slowed down. In this context, China's local authorities and industry circles are particularly concerned about the impact of emissions trading scheme (ETS), China's first major market-based approach to control greenhouse gas emissions, on competitiveness. This paper contributes to the thin empirical studies on this issue from the perspective of China's provincial industrial sub-sectors. We divide the industry of each province into 37 sub-sectors and screen the actual industrial sub-sector coverage of China's pilot ETSs. Taking advantage of the rich information of sub-sector characteristics and the longitudinal structure of our dataset over 2005-2015, we use a combination of propensity score matching technique and difference-in-difference models to analyze the impact of China's pilot ETSs on gross industrial output value (GIOV) and employment. Empirical results indicate that China's pilot ETSs have exerted a negative impact on the GIOV, and production cut is still the major approach to achieve carbon emission reductions. We also find China's pilot ETSs have led to a significant decrease in employment of the covered industrial sub-sectors. Several robustness checks confirm our findings. Further, our discussions suggest that in the short term, China's pilot ETSs have not promoted the "decoupling" of carbon emissions and economic outputs in industrial sub-sectors. While achieving carbon emission reductions, the pilot ETSs have failed to avoid a negative impact on competitiveness. Lastly, we suggest that competent authorities should prudently tailor the quota allocation methods according to sectorial conditions and consider setting up compensation measures, and covered enterprises should incorporate low-carbon development concept and address the challenges proactively from the long run.
Assuntos
Gases de Efeito Estufa , Indústrias , Carbono , China , Desenvolvimento EconômicoRESUMO
Although traditional EGFR-TKIs have advanced the treatment landscape of NSCLC with sensitive driver mutations (del19 or L858R), some NSCLC patients with EGFR exon 20 insertion mutations have been left with few effective therapies. The development of novel TKIs is still in progress. Herein, we describe the structure-guided design of a novel selective and orally bioavailable inhibitor, YK-029A, which could overcome both the T790 M mutations and exon 20 insertion of EGFR. YK-029A inhibited EGFR signaling, suppressed sensitive mutations and ex20ins of EGFR-driven cell proliferation, and was largely effective with oral administration in vivo. Furthermore, YK-029A exhibited significant antitumor activity in EGFRex20ins-driven patients-derived xenograft (PDX) models, preventing tumor progression or causing tumor regression at well-tolerated dosages. Based on the outcomes of preclinical efficacy and safety studies, YK-029A will enter phase â ¢ clinical trials for the treatment of EGFRex20ins NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutagênese Insercional , Receptores ErbB/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Mutação , Éxons , Modelos Animais de Doenças , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
A novel series of P3 oxo-modified macrocyclic hepatitis C virus NS3/4A serine protease inhibitor was designed, synthesized and biologically evaluated. The hydroxy-substituted inhibitor 10 demonstrated high potency in genotype 1a and 1b replicon and in the panel of HCV protease mutants. Interestingly, the t-butyl carbonate analog 9c, while not the most potent one in this series, exhibited a virtually flat potency profile in the panel of HCV protease mutants, thus providing opportunity for further optimization.
Assuntos
Descoberta de Drogas , Hepacivirus/efeitos dos fármacos , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Ciclopropanos , Hepacivirus/genética , Humanos , Hidroxilação , Concentração Inibidora 50 , Isoindóis , Lactamas/química , Lactamas/farmacologia , Lactamas Macrocíclicas , Estrutura Molecular , Mutação , Prolina/análogos & derivados , Inibidores de Proteases/química , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
We have synthesized and evaluated a series of novel HCV NS3 protease inhibitors with various P4 capping groups, which include urea, carbamate, methoxy-carboxamide, cyclic carbamate and amide, pyruvic amide, oxamate, oxalamide and cyanoguanidine. Most of these compounds are remarkably potent, exhibiting single-digit to sub-nanomolar activity in the enzyme assay and cell-based replicon assay. Selected compounds were also evaluated in the protease-inhibitor-resistant mutant transient replicon assay, and they were found to show quite different potency profiles against a panel of HCV protease-inhibitor-resistant mutants.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Amidas/química , Animais , Antivirais/química , Carbamatos/química , Relação Dose-Resposta a Droga , Farmacorresistência Viral/genética , Guanidinas/química , Hepacivirus/enzimologia , Hepacivirus/genética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ácido Oxâmico/química , Ratos , Inibidores de Serina Proteinase/química , Relação Estrutura-Atividade , Ureia/química , Proteínas não Estruturais Virais/metabolismoRESUMO
We describe the synthesis and potency of a novel series of N-substituted 2-phenyl- and 2-methyl-2-phenyl-1,4-diaminobutane- based CCR5 antagonists. Compounds 7a and 12f were found to be potent in anti-HIV assays and bioavailable in the low-dose rat PK model.
Assuntos
Fármacos Anti-HIV/síntese química , Antagonistas dos Receptores CCR5 , Putrescina/química , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Modelos Animais de Doenças , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Concentração Inibidora 50 , Ratos , Ratos Sprague-DawleyRESUMO
A novel series of cyclic urea-based CCR5 antagonists was designed aiming to resolve instability issue in the fasted simulated intestinal fluid (FSIF) associated with the acyclic urea moiety in 1. This class of CCR5 compounds demonstrated high antiviral activities against HIV-1 infection in both HOS and PBL assays. Further evaluation of these compounds indicated that 16-R not only substantially enhanced its stability, but also exhibited excellent pharmacokinetics properties.
Assuntos
Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5 , Descoberta de Drogas , Ureia/química , Ureia/farmacologia , Fármacos Anti-HIV/química , HIV-1/efeitos dos fármacosRESUMO
A novel series of pyridyl carboxamide-based CCR5 inhibitors was designed, synthesized, and demonstrated to be highly potent against HIV-1 infection in both HOS and PBL assays. Attempts to evaluate this series of compounds in a rat PK model revealed its instability in rat plasma. A hypothesis for this liability was proposed, and strategies to overcome this issue were pursued, leading to discovery of highly potent 40 and 41, which featured dramatically improved rat PK profiles.
Assuntos
Fármacos Anti-HIV/farmacocinética , Antagonistas dos Receptores CCR5 , Ácidos Carboxílicos/farmacocinética , Amidas/química , Animais , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/química , Ácidos Carboxílicos/sangue , Ácidos Carboxílicos/química , Descoberta de Drogas , RatosRESUMO
We have synthesized and evaluated a new series of acyclic P4-benzoxaborole-based HCV NS3 protease inhibitors. Structure-activity relationships were investigated, leading to the identification of compounds 5g and 17 with low nanomolar potency in the enzymatic and cell-based replicon assay. The linker-truncated compound 5j was found to exhibit improved absorption and oral bioavailability in rats, suggesting that further reduction of molecular weight and polar surface area could result in improved drug-like properties of this novel series.
Assuntos
Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
The Carbon Offsetting and Reduction Scheme for International Aviation (CORSIA) is the first programme to tackle carbon dioxide (CO2) emissions from a single industry at the global level, to realize the carbon-neutral growth of international flights from 2020 onwards. However, the COVID-19 pandemic has caused a drastic decline in the global aviation industry. The International Civil Aviation Organization (ICAO) has adjusted the CORSIA by removing 2020 emissions from the baseline, which now will only be based on 2019 emissions. We estimate that the total carbon dioxide (CO2) emissions from global international flights decreased by 70 % from February to July 2020 compared to those in 2019. Our analysis suggests that the annual CO2 emissions from international flights during the pilot stage of CORSIA (2021-2023) will be far below the revised baseline even if the global aviation industry could embrace an optimistic recovery. The major airline companies will have very limited motivations due to the CORSIA scheme to implement mitigation actions proactively. Therefore, more progressive actions are needed to align the industry recovery of global aviation and climate change mitigation during the post-COVID-19 period.
Assuntos
Aviação , COVID-19 , Corsiaceae , Dióxido de Carbono/análise , Humanos , Motivação , Pandemias , SARS-CoV-2RESUMO
The energy-only-market implemented in China cannot strongly support large-scale renewable energy expansion because the renewable energy expansion may disorderly phase out non-renewable power capacity. However, non-renewable power capacity, particularly the coal-fired power capacity in China, can provide vital power system adequacy needed by renewable energy expansion. We introduce capacity payments to orderly retire current coal-fired power capacity by transforming some of it into reserve capacity in order to support renewable energy expansion. Using generation and transmission expansion results from the SWITCH-China model, this paper proposes an orderly retirement path based on the assumption of implementing capacity payments. Our results show that roughly 100-200 gigawatts (GW) of coal-fired power capacity can continue to serve through 2050, and most of it is used as reserve capacity. Capacity payments of 400-700 billion yuan are needed to achieve this retirement path, and a higher adequacy requirement needs higher payments.
RESUMO
Modification of the acyl moiety in the CCR5 lead molecule 2 led to identification of several new classes of CCR5 antagonists. Antiviral activity and pharmacokinetic properties of the synthesized compounds were evaluated. Structure-activity relationship (SAR) derived from these studies further guided the optimization efforts, ultimately leading to the discovery of 36 with an acceptable drug-like profile.
Assuntos
Fármacos Anti-HIV/química , Antagonistas dos Receptores CCR5 , HIV-1/efeitos dos fármacos , Ureia/análogos & derivados , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Linhagem Celular Tumoral , Cães , Avaliação Pré-Clínica de Medicamentos , Haplorrinos , Humanos , Piridinas/química , Ratos , Receptores CCR5/metabolismo , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/farmacocinética , Replicação Viral/efeitos dos fármacosRESUMO
Several series of carbamate, urea and carboxamide-based CCR5 antagonists have been discovered via optimizations at the amine portion of lead compound 2. All compounds were evaluated for their antiviral activities. Lead urea 29 showed good pharmacokinetic properties, justifying further development of this series.
Assuntos
Aminas/química , Fármacos Anti-HIV/química , Antagonistas dos Receptores CCR5 , HIV-1/efeitos dos fármacos , Compostos de Fenilureia/química , Sulfonamidas/química , Ureia/análogos & derivados , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Humanos , Compostos de Fenilureia/síntese química , Compostos de Fenilureia/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptores CCR5/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética , Ureia/síntese química , Ureia/farmacocinética , Replicação Viral/efeitos dos fármacosRESUMO
We disclose here a series of P4-benzoxaborole-substituted macrocyclic HCV protease inhibitors. These inhibitors are potent against HCV NS3 protease, their anti-HCV replicon potencies are largely impacted by substitutions on benzoxaborole ring system and P2∗ groups. P2∗ 2-thiazole-isoquinoline provides best replicon potency. The in vitro SAR studies and in vivo PK evaluations of selected compounds are described herein.
Assuntos
Antivirais/síntese química , Hepacivirus/enzimologia , Compostos Macrocíclicos/química , Inibidores de Proteases/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Animais , Antivirais/química , Antivirais/farmacocinética , Isoquinolinas/química , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacocinética , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Ratos , Relação Estrutura-Atividade , Tiazóis/química , Proteínas não Estruturais Virais/metabolismoRESUMO
HCV NS3/4A serine protease is essential for the replication of the HCV virus and has been a clinically validated target. A series of HCV NS3/4A protease inhibitors containing a novel acylsulfamoyl benzoxaborole moiety at the P1' region was synthesized and evaluated. The resulting P1-P3 and P2-P4 macrocyclic inhibitors exhibited sub-nanomolar potency in the enzymatic assay and low nanomolar activity in the cell-based replicon assay. The in vivo PK evaluations of selected compounds are also described.
Assuntos
Compostos de Boro/química , Hepacivirus/enzimologia , Inibidores de Proteases/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Animais , Compostos de Boro/síntese química , Compostos de Boro/farmacocinética , Domínio Catalítico , Hepacivirus/efeitos dos fármacos , Masculino , Modelos Moleculares , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Ratos , Ratos Sprague-Dawley , Replicação Viral/efeitos dos fármacosRESUMO
A series of 4,4-disubstituted cyclohexylamine based CCR5 antagonists has been designed and synthesized. Their antiviral structure-activity relationship has been extensively explored.
Assuntos
Fármacos Anti-HIV/síntese química , Antagonistas dos Receptores CCR5 , Cicloexilaminas/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Linhagem Celular Tumoral , Cicloexilaminas/química , Cicloexilaminas/farmacologia , Infecções por HIV/tratamento farmacológico , Humanos , Receptores CCR5/metabolismo , Relação Estrutura-AtividadeRESUMO
Several series of CCR5 antagonists have been discovered by derivatization at the N-terminal of the piperidine ring of the core template 2. Some derivatives exhibited potent inhibition against HIV-1infection. The pharmacokinetic properties of the lead compounds 11a, 14a, 15b, and 16b have been evaluated in vivo.
Assuntos
Fármacos Anti-HIV/síntese química , Antagonistas dos Receptores CCR5 , Infecções por HIV/tratamento farmacológico , Piperidinas/síntese química , Animais , Fármacos Anti-HIV/farmacologia , Células CHO , Química Farmacêutica/métodos , Cricetinae , Cricetulus , Desenho de Fármacos , HIV-1/metabolismo , Concentração Inibidora 50 , Conformação Molecular , Piperidinas/farmacologia , Estrutura Terciária de Proteína , Ratos , Receptores CCR5/químicaRESUMO
We recently reported the discovery of preclinical CCR5 inhibitor GSK214096, 1 (J. Med. Chem. 2011, 54, 756). Detailed characterization of 1 revealed that it exists as a mixture of four separable atropisomers A-D. The two slow-interconverting pairs of rotamers A + B and C + D were separated and further characterized. HIV and CCR5-mediated chemotaxis data strongly suggest that the antiviral potency of 1 is due to rotamers A + B and not C + D. Furthermore, integrated UV, vibrational circular dichroism VCD and computational approach allowed to determine the M chirality in C + D (and P chirality in A + B). These findings imply additional avenues to be pursued toward new CCR5 antagonists.