ABSTRACT
OBJECTIVE: BAT1706 is a proposed biosimilar of bevacizumab (BEV). The objective of this phase I clinical trial was to establish pairwise similarity between BAT1706, US-sourced BEV (US-BEV), and EU-sourced BEV (EU-BEV) after a single intravenous (IV) infusion in healthy male subjects. METHODS: This phase I clinical trial was a randomized, double-blinded, three-arm study in 128 healthy adult male subjects. Every subject received a single IV infusion of 1 mg/kg of study drug and was subsequently monitored for 14 weeks. Pharmacokinetic, safety, and immunogenicity data were collected from each patient. The primary pharmacokinetic endpoint of this clinical study was area under the concentration curve from time zero to infinity (AUC0-inf). Biosimilarity of the study drugs was confirmed if the two-sided 90% confidence interval (CI) ratios of the geometric means for the three pairwise comparisons were contained within the range 80-125%. Other pharmacokinetic parameters including area under the concentration curve to time t (AUC0-t), maximum concentration of drug in plasma (Cmax), half-life (t½), and time to Cmax (tmax) were also measured. RESULTS: The pharmacokinetic parameters were comparable for the three drug products evaluated. The 90% CI for the AUC0-inf was 99-112% for BAT1706 versus EU-BEV, 97-110% for BAT1706 vs US-BEV and 92-104% for EU-BEV versus US-BEV comparisons, respectively, demonstrating biosimilarity. There were no significant adverse events attributable to BAT1706, as compared to EU-BEV and US-BEV. BAT1706 demonstrated a similar safety profile to EU-BEV and US-BEV. In addition, no anti-drug antibody positive result was reported for any subject included in the study. CONCLUSION: In this study, BAT1706, a proposed biosimilar of BEV, was shown to be highly similar to EU-BEV and US-BEV in terms of pharmacokinetic equivalence, safety, and immunogenicity in healthy subjects after a single IV infusion. TRIAL REGISTRATION: NCT03030430.
Subject(s)
Bevacizumab/pharmacokinetics , Biosimilar Pharmaceuticals/pharmacokinetics , Adult , Area Under Curve , Double-Blind Method , Healthy Volunteers , Humans , Infusions, Intravenous/methods , Male , Plasma/metabolism , Therapeutic Equivalency , Young AdultABSTRACT
A search for noncarbohydrate sLe(x) mimics led to the development of quinic acid derivatives as selectin inhibitors. At Wyeth we solved the first cocrystal structure of a small molecule, quinic acid, with E-selectin. In the cocomplex two hydroxyls of quinic acid mimic the calcium-bound fucose of the tetrasaccharide sLe(x). The X-ray structure, together with structure based computational methods, was used to design quinic acid based libraries that were synthesized and evaluated for their ability to block the interaction of sLex with P-selectin. A large number of analogues were prepared using solution-phase parallel synthesis. Selected compounds showed decrease in leukocyte rolling in the IVM mouse model. Compound 2 inhibited neutrophil influx in the murine TIP model and demonstrated good plasma exposure.
Subject(s)
E-Selectin/metabolism , Oligosaccharides/chemistry , Quinic Acid/analogs & derivatives , Quinic Acid/pharmacology , Animals , Binding Sites , Crystallography, X-Ray , Drug Design , Fucose , Jugular Veins/drug effects , Jugular Veins/physiology , Kinetics , Lewis Blood Group Antigens , Magnetic Resonance Spectroscopy , Male , Models, Molecular , Molecular Conformation , Molecular Structure , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/physiology , Oligosaccharides/chemical synthesis , Oligosaccharides/pharmacology , Rats , Rats, Sprague-Dawley , Sialyl Lewis X Antigen , Surface Plasmon ResonanceABSTRACT
Nonimmunosuppressant ligands, exemplified by GPI 1046 (1), for the peptidyl-prolyl isomerase FKBP12 have been found to unexpectedly possess powerful neuroprotective and neuroregenerative effects in vitro and in vivo. We have extensively explored the therapeutic utility of FKBP12 ligands based on analogues of proline and pipecolic acid. As part of our ongoing program to explore novel structural classes of FKBP12 ligands, we herein wish to report a new class of FKBP12 ligands containing aza-proline and aza-pipecolic acid analogues. Details of the synthetic studies, together with biological activity will be presented.
Subject(s)
Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/pharmacology , Pipecolic Acids/chemical synthesis , Pipecolic Acids/pharmacology , Proline/analogs & derivatives , Tacrolimus Binding Protein 1A/metabolism , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/antagonists & inhibitors , Animals , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Aza Compounds/pharmacology , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Dose-Response Relationship, Drug , Ligands , Male , Mice , Mice, Inbred Strains , Models, Molecular , Neuroprotective Agents/chemistry , Pipecolic Acids/chemistry , Proline/chemical synthesis , Proline/chemistry , Proline/pharmacology , Structure-Activity Relationship , Tacrolimus Binding Protein 1A/chemistry , Tyrosine 3-Monooxygenase/metabolismABSTRACT
As part of our ongoing program to explore novel structural classes of FKBP12 ligands, we herein wish to report a new class of FKBP12 ligands containing chiral bicyclic proline analogues. Details of the synthetic routes, together with preliminary biological activity, will be presented.
Subject(s)
Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/pharmacology , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/pharmacology , Proline/analogs & derivatives , Tacrolimus Binding Protein 1A/drug effects , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Animals , Binding Sites , Dopamine Agents , Indicators and Reagents , Ligands , Male , Mice , Models, Molecular , Molecular Conformation , Parkinson Disease, Secondary/chemically induced , Parkinson Disease, Secondary/drug therapy , Proline/chemical synthesis , Proline/pharmacology , Structure-Activity RelationshipABSTRACT
Rapid computational mining of large 3D molecular databases is central to generating new drug leads. Accurate virtual screening of large 3D molecular databases requires consideration of the conformational flexibility of the ligand molecules. Ligand flexibility can be included without prohibitively increasing the search time by docking ensembles of precomputed conformers from a conformationally expanded database. A pharmacophore-based docking method whereby conformers of the same or different molecules are overlaid by their largest 3D pharmacophore and simultaneously docked by partial matches to that pharmacophore is presented. The method is implemented in DOCK 4.0.
Subject(s)
Algorithms , Drug Design , Binding Sites , Binding, Competitive , Databases, Protein , HIV Protease/chemistry , Ligands , Methotrexate/chemistry , Methylurea Compounds/chemistry , Models, Molecular , NADP/chemistry , Protein Conformation , Proteins/chemistry , Pyridines/chemistry , Tetrahydrofolate Dehydrogenase/chemistryABSTRACT
The selectins are a family of cell-adhesion proteins that mediate the rolling of leukocytes on activated endothelial cells through the recognition of the carbohydrate epitope sialyl Lewis(x) (sLe(x)). Control of the leukocyte-endothelial cell adhesion process may prove useful in cases where excess recruitment of leukocytes can contribute to acute diseases such as stroke and reperfusion injury and chronic diseases such as psoriasis and rheumatoid arthritis. The development of molecules that block the interactions between sLe(x) and the selectins has become an active area of research. In this review, we will highlight the various approaches taken toward the development of sLe(x) mimetics as antagonists of E- and P-selectin, including the use of structural information about the selectins and their interactions with sLe(x) that have been revealed through the use of NMR, protein crystallography and molecular modeling.
Subject(s)
Drug Design , E-Selectin/chemistry , Molecular Mimicry , Oligosaccharides/chemistry , P-Selectin/chemistry , Animals , Carbohydrate Sequence , Cell Adhesion/drug effects , E-Selectin/metabolism , Humans , Molecular Sequence Data , Oligosaccharides/metabolism , P-Selectin/metabolism , Sialyl Lewis X AntigenABSTRACT
Potential E- and P-selectin inhibitors were synthesized to explore a hydrophobic area on the E-selectin surface and the PSGL-1 protein binding site on the P-selectin surface that was recently defined by crystallography. Three series of mannose-based compounds (libraries A, B, and C) were synthesized using solution phase parallel synthesis. Biological evaluation of these compounds was done using two ELISA-based assays and transferred NOE (trNOE) experiments. Some of the compounds showed better activity than sLe(x) in the P-selectin assay.
