ABSTRACT
Mini-tablets are advantageous over liquid formulations in overcoming challenges related to stability, taste, and dosage. This open-label, single-dose, cross-over study investigated the acceptability and safety of drug-free, film-coated mini-tablets in children aged 1 month-6 years (stratified: 4-6 years, 2-<4 years, 1-<2 years, 6-<12 months, and 1-<6 months), and their preference for swallowing either a high quantity of 2.0 mm or a low quantity of 2.5 mm diameter mini-tablets. The primary endpoint was acceptability derived from swallowability. The secondary endpoints were investigator-observed palatability, acceptability as a composite endpoint derived from both swallowability and palatability, and safety. Of 320 children randomized, 319 completed the study. Across all tablet sizes, quantities and age groups, acceptability rates based on swallowability were high (at least 87%). Palatability was rated as "pleasant/neutral" in 96.6% of children. The acceptability rates as per the composite endpoint were at least 77% and 86% for the 2.0 mm and 2.5 mm film-coated mini-tablets, respectively. No adverse events or deaths were reported. Recruitment in the 1-<6-months group was stopped early due to coughing-evaluated as "choked on" in three children. Both 2.0 mm and 2.5 mm film-coated mini-tablets are suitable formulations for young children.
ABSTRACT
Acute kidney injury (AKI) is a life-threatening disease with no known curative or preventive therapies. Data from multiple animal models and human studies have linked dysregulation of bone morphogenetic protein (BMP) signaling to AKI. Small molecules that potentiate endogenous BMP signaling should have a beneficial effect in AKI. We performed a high-throughput phenotypic screen and identified a series of FK506 analogs that act as potent BMP potentiators by sequestering FKBP12 from BMP type I receptors. We further showed that calcineurin inhibition was not required for this activity. We identified a calcineurin-sparing FK506 analog oxtFK through late-stage functionalization and structure-guided design. OxtFK demonstrated an improved safety profile in vivo relative to FK506. OxtFK stimulated BMP signaling in vitro and in vivo and protected the kidneys in an AKI mouse model, making it a promising candidate for future development as a first-in-class therapeutic for diseases with dysregulated BMP signaling.
Subject(s)
Acute Kidney Injury/drug therapy , Bone Morphogenetic Proteins/metabolism , Tacrolimus/pharmacology , Animals , Cells, Cultured , Disease Models, Animal , High-Throughput Screening Assays , Humans , Male , Mice , Mice, Inbred C57BL , Molecular Structure , Phenotype , Tacrolimus/analogs & derivatives , Tacrolimus/chemistryABSTRACT
Despite recent approvals of anti-obesity drugs there is still a high therapeutic need for alternative options with higher efficacy in humans. As part of our MCH-R1 antagonist program for the treatment of obesity, a series of biphenylacetamide HTS hits was evaluated. Several issues of the initial lead structures had to be resolved, such as potency, selectivity over related GPCRs and P-gp efflux limiting brain exposure in this series. We could demonstrate that all parameters can be significantly improved by structural modifications resulting in BI 414 as a potent and orally available MCH-R1 antagonist tool compound with acceptable in vivo efficacy in an animal model of obesity.
Subject(s)
Alkynes/chemical synthesis , Alkynes/pharmacology , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Body Weight/drug effects , Cytochrome P-450 CYP2D6/metabolism , Cytochrome P-450 Enzyme Inhibitors/chemical synthesis , Cytochrome P-450 Enzyme Inhibitors/pharmacology , Drug Design , Eating/drug effects , High-Throughput Screening Assays , Obesity/drug therapy , Rats , Receptors, G-Protein-Coupled/drug effects , Receptors, G-Protein-Coupled/metabolism , Structure-Activity RelationshipABSTRACT
Compound 4p was identified from a series of 6-hydroxy-4H-benzo[1,4]oxazin-3-ones as potent agonist of the human beta2-adrenoceptor with a high beta1/beta2-selectivity. A complete reversal of acetylcholine-induced bronchoconstriction which lasted over the whole study period of 5h was demonstrated for 4p in a guinea pig in vivo model without any signs of cardiovascular effects up to 10-fold above the first dose reaching 100% bronchoprotection. The enantiomerically pure (R)-form of 4p exerted a bronchodilatory efficacy over 24 h in dogs and guinea pigs in the absence of systemic pharmacodynamic effects. Formoterol which was tested as comparator in the same in vivo models of acetylcholine-induced bronchoconstriction did not retain efficacy after 24 h. In summary, the preclinical profile of compound (R)-4p (olodaterol, also known as BI 1744 CL) suggests a potential for once-daily dosing in man accompanied with an improved safety profile.
Subject(s)
Adrenergic beta-2 Receptor Agonists , Benzoxazines/chemistry , Benzoxazines/pharmacology , Bronchodilator Agents/chemistry , Administration, Inhalation , Animals , Benzoxazines/chemical synthesis , Bronchodilator Agents/administration & dosage , Bronchodilator Agents/pharmacology , CHO Cells , Cricetinae , Cricetulus , Dogs , Guinea Pigs , Humans , Male , Molecular Structure , Recombinant Proteins/genetics , Stereoisomerism , Treatment OutcomeABSTRACT
Beta2-adrenoceptor agonists with basic and acidic groups attached via an alkyl linker to the phenyl ethanolamine core were prepared and investigated in vitro and in vivo. The compounds exhibited a high potency in a functional cellular assay and a bronchoprotective effect in a guinea pig model which lasted over the complete study period of 5h.
