ABSTRACT
To improve wayfinding in hospitals or other complex buildings a prototype of an indoor navigation app was implemented that uses Augmented Reality for positioning and guiding users. The iOS and Android app allow the navigation from anywhere inside an area of 690 m2. In a usability test 8 from 12 users preferred using the app over a map or verbal directions. Along with the proposed improvements this approach allows covering areas as large as 100'000 m2.
Subject(s)
Augmented Reality , HospitalsABSTRACT
The structure activity relationship of the prime region of conformationally restricted hydroxyethylamine (HEA) BACE inhibitors is described. Variation of the P1' region provided selectivity over Cat-D with a series of 2,2-dioxo-isothiochromanes and optimization of the P2' substituent of chromane-HEA(s) with polar substituents provided improvements in the compound's in vitro permeability. Significant potency gains were observed with small aliphatic substituents such as methyl, n-propyl, and cyclopropyl when placed at the C-2 position of the chromane.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Chromans/chemistry , Drug Design , Enzyme Inhibitors/chemical synthesis , Binding Sites , Cells, Cultured , Ethylamines/chemical synthesis , Ethylamines/chemistry , Ethylamines/pharmacology , Inhibitory Concentration 50 , Models, Molecular , Structure-Activity RelationshipABSTRACT
Polo-like kinase-2 (Plk-2) has been implicated as the dominant kinase involved in the phosphorylation of α-synuclein in Lewy bodies, which are one of the hallmarks of Parkinson's disease neuropathology. Potent, selective, brain-penetrant inhibitors of Plk-2 were obtained from a structure-guided drug discovery approach driven by the first reported Plk-2-inhibitor complexes. The best of these compounds showed excellent isoform and kinome-wide selectivity, with physicochemical properties sufficient to interrogate the role of Plk-2 inhibition inâ vivo. One such compound significantly decreased phosphorylation of α-synuclein in rat brain upon oral administration and represents a useful probe for future studies of this therapeutic avenue toward the potential treatment of Parkinson's disease.
Subject(s)
Brain/metabolism , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , alpha-Synuclein/metabolism , Animals , Binding Sites , Blood-Brain Barrier/metabolism , Female , HEK293 Cells , Half-Life , Humans , Male , Mice , Molecular Dynamics Simulation , Phosphorylation/drug effects , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Serine-Threonine Kinases/metabolism , Protein Structure, Tertiary , Rats , Rats, Sprague-DawleyABSTRACT
A series of potent α4ß1/α4ß7 integrin inhibitors is reported, including an inhibitor 12d with remarkable oral exposure and efficacy in rat models of rheumatoid arthritis and Crohn's disease.
Subject(s)
Integrin alpha4beta1/antagonists & inhibitors , Integrins/antagonists & inhibitors , Administration, Oral , Animals , Area Under Curve , Arthritis, Rheumatoid/chemically induced , Arthritis, Rheumatoid/drug therapy , Crohn Disease/drug therapy , Disease Models, Animal , Half-Life , Humans , Integrin alpha4beta1/metabolism , Integrins/metabolism , Jurkat Cells , Microsomes, Liver/metabolism , RatsABSTRACT
Mitsunobu reactions were employed to link t-butyl esters of α4 integrin inhibitors at each of the termini of a three-arm, 40 kDa, branched PEG. Cleavage of the t-butyl esters using HCO2H provided easily isolated PEG derivatives, which are potent α4 integrin inhibitors, and which achieve sustained levels and bioactivity in vivo, following subcutaneous administration to rats.
Subject(s)
Integrin alpha4/chemistry , Polyethylene Glycols/chemistry , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacokinetics , Esters , Half-Life , Humans , Injections, Subcutaneous , Integrin alpha4/immunology , Integrin alpha4/metabolism , Jurkat Cells , RatsABSTRACT
Herein, we describe our strategy to design metabolically stable γ-secretase inhibitors which are selective for inhibition of Aß generation over Notch. We highlight our synthetic strategy to incorporate diversity and chirality. Compounds 30 (ELND006) and 34 (ELND007) both entered human clinical trials. The in vitro and in vivo characteristics for these two compounds are described. A comparison of inhibition of Aß generation in vivo between 30, 34, Semagacestat 41, Begacestat 42, and Avagacestat 43 in mice is made. 30 lowered Aß in the CSF of healthy human volunteers.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Peptides/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Heterocyclic Compounds, 3-Ring/pharmacology , Pyrazoles/pharmacology , Quinolines/pharmacology , Receptors, Notch/antagonists & inhibitors , Sulfonamides/pharmacology , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/cerebrospinal fluid , Amyloid beta-Peptides/metabolism , Animals , Area Under Curve , Basic Helix-Loop-Helix Transcription Factors/genetics , Dogs , Dose-Response Relationship, Drug , Drug Design , Drug Stability , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Gene Expression/drug effects , Heterocyclic Compounds, 3-Ring/chemistry , Homeodomain Proteins/genetics , Humans , Male , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Chemical , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/pharmacokinetics , Quinolines/chemical synthesis , Quinolines/pharmacokinetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Notch/metabolism , Structure-Activity Relationship , Sulfonamides/chemistry , Time Factors , Transcription Factor HES-1ABSTRACT
A series of (S)-2-(2-(diethylamino)-5-(N-alkyl-N-sulfonamido)pyrimidin-4-ylamino)-3-(4-(carbamoyloxy)phenyl)propanoic acid is discovered as orally available VLA-4 antagonists. Representative compounds 11b and 11p showed efficacy in multiple in vivo animal models. The in vitro selectivity of 11p is also described.
Subject(s)
Antirheumatic Agents/pharmacology , Integrin alpha4beta1/antagonists & inhibitors , Pyrimidines/pharmacology , Sulfonamides/pharmacology , Animals , Antirheumatic Agents/administration & dosage , Antirheumatic Agents/chemical synthesis , Arthritis, Experimental/drug therapy , Asthma/drug therapy , Cell Adhesion/drug effects , Collagen Type II/antagonists & inhibitors , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Fibronectins/chemistry , Humans , Mice , Mice, Inbred C57BL , Models, Molecular , Molecular Conformation , Multiple Sclerosis/drug therapy , Pyrimidines/administration & dosage , Pyrimidines/chemical synthesis , Rats , Rats, Inbred Lew , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfonamides/administration & dosage , Sulfonamides/chemical synthesisABSTRACT
Polo-like kinase-2 (Plk-2) is a potential therapeutic target for Parkinson's disease and this Letter describes the SAR of a series of dihydropteridinone based Plk-2 inhibitors. By optimizing both the N-8 substituent and the biaryl region of the inhibitors we obtained single digit nanomolar compounds such as 37 with excellent selectivity for Plk-2 over Plk-1. When dosed orally in rats, compound 37 demonstrated a 41-45% reduction of pS129-α-synuclein levels in the cerebral cortex.
Subject(s)
Drug Design , Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Administration, Oral , Animals , Brain/metabolism , Cell Cycle Proteins/antagonists & inhibitors , Cell Cycle Proteins/metabolism , HEK293 Cells , Half-Life , Humans , Mice , Microsomes, Liver/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/metabolism , Pteridines/chemical synthesis , Pteridines/chemistry , Pteridines/pharmacokinetics , Rats , Structure-Activity Relationship , Polo-Like Kinase 1ABSTRACT
Structure-activity relationship (SAR) of a novel, potent and metabolically stable series of benzo [3.2.1] bicyclic sulfonamide-pyrazoles as γ-secretase inhibitors are described. Compounds that are efficacious in reducing the cortical Aßx-40 levels in FVB mice via oral dose, as well as those with high selectivity over Notch, are highlighted.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Pyrazoles/pharmacology , Sulfonamides/pharmacology , Amyloid Precursor Protein Secretases/metabolism , Animals , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Mice , Pyrazoles/chemistry , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
INTRODUCTION: Inhibition of gamma-secretase presents a direct target for lowering Aß production in the brain as a therapy for Alzheimer's disease (AD). However, gamma-secretase is known to process multiple substrates in addition to amyloid precursor protein (APP), most notably Notch, which has limited clinical development of inhibitors targeting this enzyme. It has been postulated that APP substrate selective inhibitors of gamma-secretase would be preferable to non-selective inhibitors from a safety perspective for AD therapy. METHODS: In vitro assays monitoring inhibitor potencies at APP γ-site cleavage (equivalent to Aß40), and Notch ε-site cleavage, in conjunction with a single cell assay to simultaneously monitor selectivity for inhibition of Aß production vs. Notch signaling were developed to discover APP selective gamma-secretase inhibitors. In vivo efficacy for acute reduction of brain Aß was determined in the PDAPP transgene model of AD, as well as in wild-type FVB strain mice. In vivo selectivity was determined following seven days x twice per day (b.i.d.) treatment with 15 mg/kg/dose to 1,000 mg/kg/dose ELN475516, and monitoring brain Aß reduction vs. Notch signaling endpoints in periphery. RESULTS: The APP selective gamma-secretase inhibitors ELN318463 and ELN475516 reported here behave as classic gamma-secretase inhibitors, demonstrate 75- to 120-fold selectivity for inhibiting Aß production compared with Notch signaling in cells, and displace an active site directed inhibitor at very high concentrations only in the presence of substrate. ELN318463 demonstrated discordant efficacy for reduction of brain Aß in the PDAPP compared with wild-type FVB, not observed with ELN475516. Improved in vivo safety of ELN475516 was demonstrated in the 7d repeat dose study in wild-type mice, where a 33% reduction of brain Aß was observed in mice terminated three hours post last dose at the lowest dose of inhibitor tested. No overt in-life or post-mortem indications of systemic toxicity, nor RNA and histological end-points indicative of toxicity attributable to inhibition of Notch signaling were observed at any dose tested. CONCLUSIONS: The discordant in vivo activity of ELN318463 suggests that the potency of gamma-secretase inhibitors in AD transgenic mice should be corroborated in wild-type mice. The discovery of ELN475516 demonstrates that it is possible to develop APP selective gamma-secretase inhibitors with potential for treatment for AD.
ABSTRACT
Herein we describe further evolution of hydroxyethylamine inhibitors of BACE-1 with enhanced permeability characteristics necessary for CNS penetration. Variation at the P2' position of the inhibitor with more polar substituents led to compounds 19 and 32, which retained the potency of more lipophilic analog 1 but with much higher observed passive permeability in MDCK cellular assay.
Subject(s)
Acetamides/chemistry , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Butanols/chemistry , Cyclohexylamines/chemistry , Protease Inhibitors/chemistry , Acetamides/chemical synthesis , Acetamides/pharmacokinetics , Amyloid Precursor Protein Secretases/metabolism , Aspartic Acid Endopeptidases/metabolism , Binding Sites , Butanols/chemical synthesis , Butanols/pharmacokinetics , Cell Membrane Permeability/drug effects , Crystallography, X-Ray , Cyclohexylamines/chemical synthesis , Cyclohexylamines/pharmacokinetics , Humans , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Structure-Activity RelationshipABSTRACT
Using structure-guided design, hydroxyethylamine BACE-1 inhibitors were optimized to nanomolar Abeta cellular inhibition with selectivity against cathepsin-D. X-ray crystallography illuminated the S1' residues critical to this effort, which culminated in compounds 56 and 57 that exhibited potency and selectivity but poor permeability and high P-gp efflux.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/chemistry , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Drug Design , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Amyloid Precursor Protein Secretases/chemistry , Amyloid Precursor Protein Secretases/genetics , Aspartic Acid Endopeptidases/chemistry , Aspartic Acid Endopeptidases/genetics , Humans , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Substrate SpecificityABSTRACT
In this Letter, we report our strategy to design potent and metabolically stable gamma-secretase inhibitors that are efficacious in reducing the cortical Abetax-40 levels in FVB mice via a single PO dose.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Protease Inhibitors/chemical synthesis , Pyrazoles/chemistry , Quinolines/chemistry , Sulfonamides/chemistry , Administration, Oral , Amyloid Precursor Protein Secretases/metabolism , Animals , Drug Design , Mice , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Structure-Activity RelationshipABSTRACT
The design and synthesis of a novel series of potent and cell permeable peptidomimetic inhibitors of the human beta-secretase (BACE) are described. These inhibitors feature a hydroxyethyl secondary amine isostere and a novel aromatic ring replacement for the C-terminus. The crystal structure of BACE in complex with this hydroxyethyl secondary amine isostere inhibitor is also presented.
