ABSTRACT
A novel series of 5-membered heterocycle-containing phenylpropanoic acid derivatives was discovered as potent GPR120 agonists with low clearance, high oral bioavailability and in vivo antidiabetic activity in rodents.
Subject(s)
Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Phenylpropionates/chemistry , Phenylpropionates/pharmacology , Receptors, G-Protein-Coupled/agonists , Animals , Biological Availability , Blood Glucose/analysis , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Drug Design , HEK293 Cells , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacokinetics , Heterocyclic Compounds/pharmacology , Heterocyclic Compounds/therapeutic use , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Mice, Inbred C57BL , Phenylpropionates/pharmacokinetics , Phenylpropionates/therapeutic use , Receptors, G-Protein-Coupled/metabolism , Structure-Activity RelationshipABSTRACT
Novel antibacterial fluoroquinolone agents bearing a 4-alkylidenylpiperidine 7-position substituent are active against quinolone-susceptible and quinolone-resistant gram-positive bacteria, including Streptococcus pneumoniae and MRSA. Analogs 22b, 23c, and 24 demonstrated superior in vitro and in vivo efficacy to ciprofloxacin against these cocci.
Subject(s)
Anti-Bacterial Agents/pharmacology , Gram-Positive Bacteria/drug effects , Quinolones/pharmacology , Topoisomerase Inhibitors/pharmacology , HumansABSTRACT
BACKGROUND: In the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program, canagliflozin reduced the rates of major adverse cardiovascular events and the results suggested a renal benefit in patients with type 2 diabetes who were at high risk for cardiovascular events, compared with those treated with placebo. Here we report the results of a prespecified exploratory analysis of the long-term effects of canagliflozin on a range of sustained and adjudicated renal outcomes. METHODS: The CANVAS Program consists of two double-blind, randomised trials that assessed canagliflozin versus placebo in participants with type 2 diabetes who were at high risk of cardiovascular events, done at 667 centres in 30 countries. People with type 2 diabetes and an HbA1c of 7Ā·0-10Ā·5% (53-91 mmol/mol) who were aged at least 30 years and had a history of symptomatic atherosclerotic vascular disease, or who were aged at least 50 years and had at least two cardiovascular risk factors were eligible to participate. Participants in CANVAS were randomly assigned (1:1:1) to receive 300 mg canagliflozin, 100 mg canagliflozin, or matching placebo once daily. Participants in CANVAS-R were randomly assigned (1:1) to receive canagliflozin or matching placebo, at an initial dose of 100 mg daily, with optional uptitration to 300 mg from week 13 or matching placebo. Participants and all study staff were masked to treatment allocations until study completion. Prespecified outcomes reported here include a composite of sustained and adjudicated doubling in serum creatinine, end-stage kidney disease, or death from renal causes; the individual components of this composite outcome; annual reductions in estimated glomerular filtration rate (eGFR); and changes in urinary albumin-to-creatinine ratio (UACR). The trials are registered with ClinicalTrials.gov, numbers NCT01032629 (CANVAS) and NCT01989754 (CANVAS-R). FINDINGS: Between Nov 17, 2009, and March 7, 2011 (CANVAS), and Jan 17, 2014, and May 29, 2015 (CANVAS-R), 15Ć¢ĀĀ494 people were screened, of whom 10Ć¢ĀĀ142 participants (with a baseline mean eGFR 76Ā·5 mL/min per 1Ā·73 m2, median UACR 12Ā·3 mg/g, and 80% of whom were receiving renin-angiotensin system blockade) were randomly allocated to receive either canagliflozin or placebo. The composite outcome of sustained doubling of serum creatinine, end-stage kidney disease, and death from renal causes occurred less frequently in the canagliflozin group compared with the placebo group (1Ā·5 per 1000 patient-years in the canagliflozin group vs 2Ā·8 per 1000 patient-years in the placebo group; hazard ratio 0Ā·53, 95% CI 0Ā·33-0Ā·84), with consistent findings across prespecified patient subgroups. Annual eGFR decline was slower (slope difference between groups 1Ā·2 mL/min per 1Ā·73 m2 per year, 95% CI 1Ā·0-1Ā·4) and mean UACR was 18% lower (95% CI 16-20) in participants treated with canagliflozin than in those treated with placebo. Total serious renal-related adverse events were similar between the canagliflozin and placebo groups (2Ā·5 vs 3Ā·3 per 1000 patient-years; HR 0Ā·76, 95% CI 0Ā·49-1Ā·19). INTERPRETATION: In a prespecified exploratory analysis, canagliflozin treatment was associated with a reduced risk of sustained loss of kidney function, attenuated eGFR decline, and a reduction in albuminuria, which supports a possible renoprotective effect of this drug in people with type 2 diabetes. FUNDING: Janssen Research & Development.
Subject(s)
Canagliflozin/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Kidney Diseases/drug therapy , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Adult , Albuminuria , Canagliflozin/adverse effects , Creatinine/blood , Creatinine/urine , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/pathology , Female , Glomerular Filtration Rate/drug effects , Humans , Kidney Diseases/etiology , Kidney Diseases/pathology , Male , Proportional Hazards Models , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Treatment OutcomeABSTRACT
At least 18 antibacterial agents are currently undergoing clinical trials for the treatment of infections caused by susceptible and resistant bacteria. The beta-lactam class includes new parenteral carbapenems and cephalosporins with varying spectra of activities. The glycopeptides are antibiotics with in vitro activity primarily against Gram-positive bacteria, including multi-resistant strains. Three quinolones are being investigated for use against a variety of Gram-positive and respiratory Gram-negative organisms. Several other classes of antibacterial agents currently in clinical trials are represented by a glycolipodepsipeptide, a dihydrofolate reductase inhibitor, an oxazolidinone, two peptide antibiotics, a glycylcycline, and a peptide deformylase inhibitor, a member of a new antibacterial class.
Subject(s)
Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Bacteria/drug effects , Bacterial Infections/drug therapy , Anti-Bacterial Agents/chemistry , Clinical Trials as Topic , Drug Evaluation , HumansABSTRACT
Benzonitrile oxides undergo 1,3-dipolar cycloaddition reactions with methyl cinnamate to produce the 5-phenyl and 4-phenyl regioisomers in approximately an 80:20 ratio. However, use of N,N-diethylcinnamide as the dipolarophile unexpectedly resulted in the formation of the 5-phenyl and 4-phenyl regioisomers in a 23:77 ratio. Studies have shown that this phenomena occurs only for tertiary cinnamides. In addition, it has been demonstrated that the phenyl group of tertiary cinnamides is not essential for the reversal of regioselectivity since crotonamides produce the same results and trends as the cinnamides. However, since acrylates and acrylamides both produce the 5-carbonyl regioisomers, it can be concluded that the beta-substituent is playing a key role for the unexpected results by possibly increasing steric interactions between the dipole and dipolarophile in the transition state. Transition state energies were calculated for the regioisomeric cycloadduct pairs derived from several crotonamides as well as methyl crotonate. These calculations indicate that steric factors are indeed responsible for the reversal of regioselectivity.
Subject(s)
Diagnostic Imaging , Mass Screening , Mobile Health Units , Humans , India , Rural PopulationABSTRACT
A series of pyrrolopyridine-substituted oxazolidinones containing various C-5 acetamide isosteres was synthesized and the structure-antibacterial activity relationships determined against a representative panel of susceptible and resistant Gram-positive bacteria.
Subject(s)
Acetamides/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Oxazolidinones/chemistry , Oxazolidinones/pharmacology , Pyridines/chemistry , Anti-Bacterial Agents/chemistry , Enterococcus/drug effects , Linezolid , Molecular Structure , Oxazolidinones/chemical synthesis , Staphylococcus aureus/drug effects , Structure-Activity RelationshipABSTRACT
Oxazolidinone antibacterial agents, where the morpholino group of linezolid was replaced with an N-substituted piperidinyloxy moiety, were synthesized and shown to be active against a variety of resistant and susceptible Gram-positive organisms. The functionality attached to the piperidine nitrogen was varied extensively to determine the SAR for this series. One of the most potent compounds, 11, showed in vivo efficacy upon subcutaneous administration in a Staphylococcus aureus Smith murine systemic infection.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Oxazolidinones/chemistry , Oxazolidinones/pharmacology , Animals , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Magnetic Resonance Spectroscopy , Mass Spectrometry , Mice , Microbial Sensitivity Tests , Structure-Activity RelationshipABSTRACT
A series of oxazolidinone antibacterial agents containing a 5-substituted isoxazol-3-yl moiety were synthesized via a nitrile oxide [3+2] dipolar cycloaddition reaction. These compounds were screened against a panel of susceptible and resistant Gram-positive organisms. Several analogs from this series were comparable to or more potent than linezolid in vitro.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Isoxazoles/chemical synthesis , Oxazolidinones/chemical synthesis , Animals , Anti-Bacterial Agents/pharmacology , Drug Evaluation, Preclinical/methods , Female , Isoxazoles/pharmacology , Mice , Microbial Sensitivity Tests/methods , Oxazolidinones/pharmacologyABSTRACT
A novel series of oxazolidinones containing a pyrroloaryl substituent was synthesized and screened against a representative panel of susceptible and resistant Gram-positive bacteria. Several members of this series were found to have antibacterial activity comparable to or better than linezolid.
Subject(s)
Acetamides/chemical synthesis , Acetamides/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Gram-Positive Bacteria/drug effects , Oxazolidinones/chemical synthesis , Oxazolidinones/pharmacology , Acetamides/chemistry , Anti-Bacterial Agents/chemistry , Linezolid , Microbial Sensitivity Tests , Oxazolidinones/chemistry , Structure-Activity RelationshipABSTRACT
A novel series of 3,5-diarylisoxazole and 3,5-diaryl-1,2,4-oxadiazole IL-8 inhibitors has been identified. These compounds exhibit activity in an IL-8 binding assay as well as in a functional assay of IL-8 induced elastase release from neutrophils. In addition, one of the compounds exhibits oral activity in a rat adjuvant arthritis model.