RESUMO
Everyone is making constant efforts to establish an effective diagnostic approach, therapy and control of the spread of the pandemic. Due to a flexible formulation, the parameters prior to the normal distributions and explicitly formulate assumptions on the transition probabilities between these categories over time. The spread of the COVID-19 pandemic represents a serious threat for scientists and academics, health professionals and even governments today. The Hospital wards are classified into Intensive Care Unit (ICU), Regular Wards (RW) with Recovered (R) and Deceased (D).. The formulation may be truncated to include particular hypotheses with an epidemiological interpretation. The principles of Three-Way Decision Theory could be used to anticipate and diagnose COVID-19 patients were classified into one of three zones based on their symptoms: Positive, Negative, or Boundary, and treatment are recommended if necessary. The thresholds that distinguish the three zones are determined using a variance-based criterion. Examine the impact of nonpharmaceutical interventions and the findings from data gathered during the second wave of the pandemic in Trivandrum, India.The Three-Way Decision Theory model has a good fit and gives good predictive performance, especially for RW and ICU patients, according to suitable discrepancy metrics that were created to assess and compare models. 95 percent accuracy increased and calculated values for 10 days to demonstrate the temporal aspects of the expected daily reproduction number R.
RESUMO
The discovery of potent, bioavailable small molecule inhibitors of p53-HDM2 PPI led us to investigate subsequent modifications to address a CYP3A4 time-dependent inhibition liability. On the basis of the crystal structure of HDM2 in complex with 2, further functionalization of the solvent exposed area of the molecule that binds to Phe19 pocket were investigated as a strategy to modulate the molecule liphophilicity. Introduction of 2-oxo-nicotinic amide at Phe19 proved a viable strategy in obtaining inhibitors exempt from CYP3A4 time-dependent inhibition liability.
Assuntos
Citocromo P-450 CYP3A/metabolismo , Fenilalanina/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Proteína Supressora de Tumor p53/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Fenilalanina/química , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/metabolismoRESUMO
The discovery of 3,3-disubstituted piperidine 1 as novel p53-HDM2 inhibitors prompted us to implement subsequent SAR follow up directed towards piperidine core modifications. Conformational restrictions and further functionalization of the piperidine core were investigated as a strategy to gain additional interactions with HDM2. Substitutions at positions 4, 5 and 6 of the piperidine ring were explored. Although some substitutions were tolerated, no significant improvement in potency was observed compared to 1. Incorporation of an allyl side chain at position 2 provided a drastic improvement in binding potency.
Assuntos
Piperidinas/síntese química , Piperidinas/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/antagonistas & inibidores , Bioensaio , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Piperidinas/química , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/metabolismoRESUMO
Identification of low-dose, low-molecular-weight, drug-like inhibitors of protein-protein interactions (PPIs) is a challenging area of research. Despite the challenges, the therapeutic potential of PPI inhibition has driven significant efforts toward this goal. Adding to recent success in this area, we describe herein our efforts to optimize a novel purine carboxylic acid-derived inhibitor of the HDM2-p53 PPI into a series of low-projected dose inhibitors with overall favorable pharmacokinetic and physical properties. Ultimately, a strategy focused on leveraging known binding hot spots coupled with biostructural information to guide the design of conformationally constrained analogs and a focus on efficiency metrics led to the discovery of MK-4688 (compound 56), a highly potent, selective, and low-molecular-weight inhibitor suitable for clinical investigation.
Assuntos
Imidazóis/química , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Piridinas/química , Proteína Supressora de Tumor p53/antagonistas & inibidores , Humanos , Ligação Proteica , Proteínas Proto-Oncogênicas c-mdm2/química , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/metabolismoRESUMO
A highly efficient and practical route to 3,4-isopropylidene proline I, starting from (+)-3-carene, was developed. The three continuous stereocenters were constructed using the inherent chirality of the starting natural product 2. The overall yield for the 12-step synthesis is 34%. The optimized sequence leading to 1 has been successfully applied on a multigram scale, thereby establishing the practicality of this route.
Assuntos
Compostos Alílicos/síntese química , Monoterpenos/química , Prolina/análogos & derivados , Prolina/síntese química , Compostos Alílicos/química , Monoterpenos Bicíclicos , Catálise , Cromatografia em Gel , Ciclização , Dados de Sequência Molecular , Estrutura Molecular , Prolina/química , EstereoisomerismoRESUMO
SAR studies on the extension of P3 unit of Boceprevir (1, SCH 503034) with amides and lactams and their synthesis is described. Extensive SAR studies resulted in the identification of 36 bearing 4, 4-dimethyl lactam as the new P4 cap unit with improved potency (K(i)( *)=15nM, EC 90=70nM) and pharmacokinetic properties (Rat AUC (PO)=3.52microMh) compared to 1.
Assuntos
Amidas/química , Antivirais/química , Lactamas/química , Oligopeptídeos/química , Inibidores de Proteases/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacocinética , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Sítios de Ligação , Cristalografia por Raios X , Lactamas/síntese química , Lactamas/farmacocinética , Oligopeptídeos/síntese química , Oligopeptídeos/farmacocinética , Prolina/análogos & derivados , Prolina/química , Prolina/farmacocinética , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Ratos , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismoRESUMO
Hepatitis C (HCV) infection is a global health crisis leading to chronic liver disease. In our efforts towards a second generation HCV NS3 serine protease inhibitor with improved profile, we have undertaken SAR studies in various regions of Boceprevir including P2. Herein, we report the synthesis and structure-activity relationship studies of inhibitors with (S)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid 2 as P2 substituent replacing the (1R,2S,5S)-6,6-dimethyl 3-azabicyclo[3.1.0]hexane-2-carboxylic acid. The systematic investigation led to the discovery of highly potent inhibitor 25 (K(i)( *)=7nM, EC(90)=30nM) with improved rat exposure of 2.56microM h.
Assuntos
Antivirais/química , Prolina/análogos & derivados , Inibidores de Proteases/química , Quinolizinas/química , Compostos de Enxofre/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Sítios de Ligação , Simulação por Computador , Humanos , Prolina/síntese química , Prolina/química , Prolina/farmacocinética , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Ratos , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismoRESUMO
In the search for a second generation HCV protease inhibitor, molecular modeling studies of the X-ray crystal structure of Boceprevir1 bound to the NS3 protein suggest that expansion into the S4 pocket could provide additional hydrophobic Van der Waals interactions. Effective replacement of the P4 tert-butyl with a cyclohexylmethyl ligand led to inhibitor 2 with improved enzyme and replicon activities. Subsequent modeling and SAR studies led to the pyridine 38 and sulfone analogues 52 and 53 with vastly improved PK parameters in monkeys, forming a new foundation for further exploration.
Assuntos
Antivirais/química , Prolina/análogos & derivados , Inibidores de Proteases/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Área Sob a Curva , Disponibilidade Biológica , Cristalografia por Raios X , Haplorrinos , Modelos Moleculares , Prolina/química , Prolina/farmacocinética , Prolina/farmacologia , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Hepatitis is a disease characterized by inflammation of the liver, usually producing swelling and, in many cases, permanent damage to liver tissues. Viral hepatitis C (HCV), a small (+)-RNA virus, infects chronically 3% of the world's population. Boceprevir, SCH 503034, (1) our first generation HCV inhibitor, has already established proof-of- concept and is currently in late stage (phase III) clinical trials. In view of the positive data from our first generation compound, further work aimed at optimizing its overall profile was undertaken. Herein, we report that extension of our earlier inhibitor to the P(4) pocket by introducing a new sulfonamide moiety and optimization of the P1/P(1)' capping led to the discovery of a novel series of inhibitors of the HCV NS3 serine protease. Optimization of the P(1) residue significantly improved potency and selectivity. The combination of optimal moieties led to the discovery of compound 47 which, in addition to being a potent inhibitor of HCV subgenomic RNA replication, was also found to have good PK profile in rat, dog and monkey.
Assuntos
Amidas/química , Antivirais/química , Inibidores de Serina Proteinase/química , Sulfonamidas/química , Ureia/análogos & derivados , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Sítios de Ligação , Simulação por Computador , Cães , Avaliação Pré-Clínica de Medicamentos , Proteínas de Escherichia coli , Haplorrinos , Humanos , Proteínas de Membrana , Modelos Moleculares , Ratos , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/farmacocinética , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética , Ureia/síntese química , Ureia/química , Ureia/farmacocinética , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
Extensive SAR studies of the P3 capping group led to the discovery of a series of potent inhibitors with sultam and cyclic sulfonyl urea moieties as the P3 capping. The bicyclic thiophene-sultam or phenyl-sultam cappings were selected for further SAR development. Modification at the P3 side chain determined that the tert-butyl group was the best choice at that position. Optimization of P1 residue significantly improved potency and selectivity. The combination of optimal moieties at all positions led to the discovery of compound 33. This compound had the best overall profile in potency and PK profile: excellent K(i)(*) of 5.3 nM and activity in replicon (EC(90)) of 80 nM, extremely high selectivity of 6100, and a good rat PO AUC of 1.43 microMh.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Compostos de Sulfonilureia/síntese química , Compostos de Sulfonilureia/farmacologia , Proteínas não Estruturais Virais/efeitos dos fármacos , Administração Oral , Animais , Antivirais/química , Técnicas de Química Combinatória , Desenho de Fármacos , Estrutura Molecular , Inibidores de Proteases/química , Ratos , Relação Estrutura-Atividade , Compostos de Sulfonilureia/química , Tiazinas/químicaRESUMO
Hepatitis C Virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 200 million people worldwide. Currently the only therapeutic regimens are subcutaneous interferon-alpha or PEG-interferon alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only approximately 50% of the patients showing sustained virological response. We recently disclosed the discovery of Boceprevir, SCH 503034 (1), which is a novel, potent, selective, orally bioavailable NS3 protease inhibitor that has been shown to be efficacious in humans and is currently undergoing clinical trials. As second generation compounds, we have further explored various novel structures with the aim of improving enzyme and cellular binding activities of 1. Herein, we disclose our efforts toward the identification of a novel P(3) sulfonamide-capped inhibitor that demonstrated improved binding and cellular activity compared to 1. X-ray structure of one of these inhibitors bound to the enzyme revealed a hydrogen bond of the P(3) sulfonamide group to Cys-159 which resulted in improved binding and cellular potency.
Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Sulfonamidas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Animais , Antivirais/química , Antivirais/farmacocinética , Cristalografia por Raios X , Descoberta de Drogas , Humanos , Modelos Moleculares , Ligação Proteica , Ratos , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacocinética , Replicação Viral/efeitos dos fármacosRESUMO
The fetal origins hypothesis, proposes that non-communicable diseases including coronary heart disease, type 2 diabetes and hypertension originate through the responses of a fetus to undernutrition, that permanently change the structure and function of the body. Associations between low birthweight and disease in later life have been widely studied in Europe and the USA. Studies in southern India have shown that babies who are short and fat tend to become insulin deficient and have high rates of non-insulin dependent diabetes. These findings have important public health implications as it suggests that associations with body size at birth underestimate the contribution of intrauterine development to later disease, and also, that while the primary prevention of coronary heart disease and non-insulin dependent diabetes may ultimately depend on changing the body composition and diets of young women. Therefore, more immediate benefit may come from preventing imbalances between prenatal and postnatal growth among children. The basic premise of the thrifty gene hypothesis is that certain populations may have genes that determine increased fat storage, which in times of famine represent a survival advantage, but in a modern environment result in obesity and type 2 diabetes. The fetal origins theory is of greatest relevance to the developing world and the implications of this work for global health are enormous. To reduce chronic diseases, we need to understand how the human fetus is nourished and how malnutrition changes its physiology and metabolism, so that interventions be implemented to limit the damage. The challenge for the next decade must be to discover the cellular and molecular mechanisms giving rise to these associations. If this aim is accomplished, it might be possible to devise strategies to reduce the impact of these disabling chronic and expensive diseases.
Assuntos
Doença Crônica/prevenção & controle , Efeitos Tardios da Exposição Pré-Natal , Adulto , Doença Crônica/epidemiologia , Feminino , Desenvolvimento Fetal , Humanos , Desnutrição , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/epidemiologiaRESUMO
OBJECTIVE: To observe and compare the markers of fetal onset adult diseases among low birthweight (<2500 grams, LBW) and normal birthweight (> or =2500 grams, NBW) babies at 16 years of age. METHODS: Comparative cross sectional analysis of two groups of cohorts followed-up at 1 year and 16 years of age at Child Development Centre (CDC), Medical College, Thiruvananthapuram. 189 LBW babies formed the study group and 213 NBW babies formed the comparison group. At 16 years, the parameters used for assessment of both the groups were, body mass index (BMI) and the markers of fetal onset adult diseases fasting blood glucose level, fasting plasma insulin level, total cholesterol, low density lipoprotein, high density lipoprotein and triglycerides. RESULTS: High triglyceride values and overweight/obesity were significantly more in LBW adolescents when compared to NBW adolescents. This has policy implications in planning adolescent nutrition and care programs in India.
Assuntos
Peso ao Nascer , Recém-Nascido de Baixo Peso , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adolescente , Adulto , Índice de Massa Corporal , Doença Crônica/epidemiologia , Estudos Transversais , Feminino , Feto/fisiologia , Humanos , Recém-Nascido , Masculino , Razão de Chances , Sobrepeso/epidemiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/diagnóstico , Triglicerídeos/sangueRESUMO
The study was conducted to compare growth status, blood pressure, self esteem and intelligence of 200 low birthweight (LBW) and 224 normal birthweight (NBW) adolescents at 13 years of age. Intelligence scores at or below the 25th percentile (low performance) were observed among 51.4% LBW and 41.7% NBW adolescents (<0.05). Statistically significant lower scores for self esteem (mean difference 4.31, 95% CI 1.91-6.71) were observed among LBW adolescents. Height, weight and body mass index (BMI) were lower among all LBW adolescents and the difference reached statistical significance for weight and BMI among LBW adolescent girls.
Assuntos
Recém-Nascido de Baixo Peso/crescimento & desenvolvimento , Adolescente , Pressão Sanguínea , Seguimentos , Nível de Saúde , Humanos , Recém-Nascido , Inteligência , Exame Neurológico , AutoimagemRESUMO
A new subseries of substituted piperidines as p53-HDM2 inhibitors exemplified by 21 has been developed from the initial lead 1. Research focused on optimization of a crucial HDM2 Trp23-ligand interaction led to the identification of 2-(trifluoromethyl)thiophene as the preferred moiety. Further investigation of the Leu26 pocket resulted in potent, novel substituted piperidine inhibitors of the HDM2-p53 interaction that demonstrated tumor regression in several human cancer xenograft models in mice. The structure of HDM2 in complex with inhibitors 3, 10, and 21 is described.
RESUMO
Novel 2'-modified guanosine nucleosides were synthesized from inexpensive starting materials in 7-10 steps via hydroazidation or hydrocyanation reactions of the corresponding 2'-olefin. The antiviral effectiveness of the guanosine nucleosides was evaluated by converting them to the corresponding 5'-O-triphosphates (compounds 38-44) and testing their biochemical inhibitory activity against the wild-type NS5B polymerase.
Assuntos
Antivirais/síntese química , Nucleotídeos de Guanina/síntese química , Inibidores da Síntese de Ácido Nucleico/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Alcenos/síntese química , Azidas/síntese química , Hepacivirus/enzimologia , Proteínas não Estruturais Virais/químicaRESUMO
HCV infection affects more than 170 million people worldwide and many of those patients will reach the end stage complications of the disease which include hepatocarcinoma and liver failure. The success rate for treatment of patients infected with genotype-1 is about 40%. Therefore, novel treatments are needed to combat the infection. The HCV NS3 protease inhibitor Boceprevir (1) was reported by our research group and efforts continue for the discovery of more potent compounds with improved pharmacokinetic profiles. A new series of HCV NS3 protease inhibitors having a cyclic sulfone P3-cap have been discovered. Compounds 43 and 44 showed K(i)* values in the single-digit nM range and their cellular potency was improved by 10-fold compared to 1. The pharmacokinetic profiles of 43 and 44 in rats and monkeys were also improved to achieve higher plasma levels after oral administration.
Assuntos
Hepacivirus/enzimologia , Oligopeptídeos/síntese química , Inibidores de Serina Proteinase/síntese química , Sulfonas/síntese química , Administração Oral , Animais , Cristalografia por Raios X , Haplorrinos , Modelos Moleculares , Oligopeptídeos/farmacocinética , Oligopeptídeos/farmacologia , Ratos , Inibidores de Serina Proteinase/farmacocinética , Inibidores de Serina Proteinase/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonas/farmacocinética , Sulfonas/farmacologiaRESUMO
Boceprevir (SCH 503034), 1, a novel HCV NS3 serine protease inhibitor discovered in our laboratories, is currently undergoing phase III clinical trials. Detailed investigations toward a second generation protease inhibitor culminated in the discovery of narlaprevir (SCH 900518), 37, with improved potency (â¼10-fold over 1), pharmacokinetic profile and physicochemical characteristics, currently in phase II human trials. Exploration of synthetic sequence for preparation of 37 resulted in a route that required no silica gel purification for the entire synthesis.
RESUMO
The hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The moderate efficacy along with side effects of the current pegylated interferon and ribavirin combination therapy underscores the need for more effective and safer new treatment. In an effort to improve upon our current clinical candidate, Boceprevir (SCH 503034), extensive SAR studies were performed on the P3 capping moieties. This led to the discovery of tert-leucinol derived cyclic imides as a potent series of novel P3 capping groups. Thus, the introduction of these imide caps improved the cell-based replicon EC(90) by more than 10-fold. A number of imides with various substitutions, ring sizes, bicyclic systems, and heterocyclic rings were explored. The 4,4-dimethyl substituted glutarimide emerged as the best cap as exemplified in compound 21 (K(i)* = 4 nM, EC(90) = 40 nM). Systematic optimization of different positions (P', P3, and P1) of the inhibitor resulted in the identification of the lead compound 46, which had an excellent potency (K(i)* = 4 nM, EC(90) = 30 nM) and good pharmacokinetic profile (22% and 35% bioavailability in rats and dogs, respectively). X-ray structure of inhibitor 46 bound to the enzyme revealed that there was an additional hydrogen bonding interaction between one of the imide carbonyls and Cys159.
Assuntos
Antivirais/síntese química , Hepacivirus/enzimologia , Piperidonas/síntese química , Inibidores de Serina Proteinase/síntese química , Ureia/análogos & derivados , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Disponibilidade Biológica , Cristalografia por Raios X , Cães , Haplorrinos , Hepacivirus/genética , Ligação de Hidrogênio , Imidas/síntese química , Imidas/química , Leucina/análogos & derivados , Leucina/síntese química , Leucina/química , Modelos Moleculares , Piperidonas/farmacocinética , Piperidonas/farmacologia , Ratos , Inibidores de Serina Proteinase/farmacocinética , Inibidores de Serina Proteinase/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/farmacocinética , Ureia/farmacologiaRESUMO
Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, and affects more than 200 million people worldwide. Although combination therapy of interferon-alpha and ribavirin is reasonably successful in treating majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of a series of ketoamide derived P(1)-P(3) macrocyclic inhibitors that are more potent than the first generation clinical candidate, boceprevir (1, Sch 503034), is discussed. The optimization of these macrocyclic inhibitors identified a P(3) imide capped analogue 52 that was 20 times more potent than 1 and demonstrated good oral pharmacokinetics in rats. X-ray structure of 52 bound to NS3 protease and biological data are also discussed.