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1.
BMC Musculoskelet Disord ; 19(1): 366, 2018 Oct 12.
Article in English | MEDLINE | ID: mdl-30309332

ABSTRACT

BACKGROUND: There is a lack of evidence-based quantitative clinical methods to adequately assess posture. Our team developed a clinical photographic posture assessment tool (CPPAT) and implemented this tool in clinical practice to standardize posture assessment. The objectives were to determine the level of acceptance of the CPPAT and to document predictors as well as facilitators of and barriers to the acceptance of this tool by clinicians doing posture re-education. METHODS: This is a prospective study focussing on technology acceptance. Thirty-two clinician participants (physical therapists and sport therapists) received a 3-5 h training workshop explaining how to use the CPPAT. Over a three-month trial, they recorded time-on-task for a complete posture evaluation (photo - and photo-processing). Subsequently, participants rated their acceptance of the tool and commented on facilitators and barriers of the clinical method. RESULTS: Twenty-three clinician participants completed the trial. They took 22 (mean) ± 10 min (SD) for photo acquisition and 36 min ± 19 min for photo-processing. Acceptance of the CPPAT was high. Perceived ease of use was an indirect predictor of intention to use, mediated by perceived usefulness. Analysis time was an indirect predictor, mediated by perceived usefulness, and a marginally significant direct predictor. Principal facilitators were objective measurements, visualization, utility, and ease of use. Barriers were time to do a complete analysis of posture, quality of human-computer interaction, non-automation of posture index calculation and photo transfer, and lack of versatility. CONCLUSION: The CPPAT is perceived as useful and easy to use by clinicians and may facilitate the quantitative analysis of posture. Adapting the user-interface and functionality to quantify posture may facilitate a wider adoption of the tool.


Subject(s)
Attitude of Health Personnel , Health Knowledge, Attitudes, Practice , Musculoskeletal Diseases/diagnosis , Photography/standards , Physical Therapists/psychology , Physicians/psychology , Posture , Attitude to Computers , Canada , Europe , Humans , Image Interpretation, Computer-Assisted/standards , Musculoskeletal Diseases/physiopathology , Predictive Value of Tests , Prospective Studies , Time Factors , Workflow
2.
Bioorg Med Chem Lett ; 28(17): 2985-2992, 2018 09 15.
Article in English | MEDLINE | ID: mdl-30122227
3.
Spine J ; 18(12): 2247-2258, 2018 12.
Article in English | MEDLINE | ID: mdl-29746961

ABSTRACT

BACKGROUND CONTEXT: Posture changes are a major consequence of idiopathic scoliosis (IS). Posture changes can lead to psychosocial and physical impairments in adolescents with IS. Therefore, it is important to assess posture, but the test-retest reliability of posture measurements still remains unknown in this population. PURPOSE: The primary objective of the present study was to determine the test-retest reliability of 25 head and trunk posture indices using the Clinical Photographic Postural Assessment Tool (CPPAT) in adolescents with IS. The secondary objective was to determine the standard error of measurement and the minimal detectable change. STUDY DESIGN/SETTING: This is a prospective test-retest reliability study carried out at two tertiary university hospital centers. PATIENTS SAMPLE: Forty-one adolescents with IS, aged 10-16 years old with curves 10°-45° and treated by medical intervention, were recruited. METHODS: Two posture assessments were done using the CPPAT 5-10 days apart following a standardized procedure. Photographs were analyzed with the CPPAT software by digitizing reference landmarks placed on the participant by a physiotherapist evaluator. Generalizability theory was used to obtain a coefficient of dependability, standard error of measurement, and the minimal detectable change at 90% confidence interval. RESULTS: Fourteen of 25 posture indices had a good reliability (ϕ≥0.78), 10 had moderate reliability (ϕ=0.55-0.74), and 1 had poor reliability (ϕ=0.45). The most reliable posture indices were waist angle asymmetry (ϕ=0.93), right waist angle (ϕ=0.91), and frontal trunk list (ϕ=0.92). Right sagittal trunk list was the least reliable posture index (ϕ=0.45). The MDC90 values ranged from 2.6 to 10.3° for angular measurements and from 8.4 to 35.1 mm for linear measurements. CONCLUSIONS: The present study demonstrates that most posture indices, especially the trunk posture indices, are reproducible in time among adolescents with IS and provides reference values. Clinicians and researchers can use these reference values to assess change in posture over time attributable to treatment effectiveness.


Subject(s)
Posture , Scoliosis/pathology , Software , Adolescent , Child , Female , Humans , Male , Photography/standards , Reference Values , Reproducibility of Results
4.
J Med Chem ; 61(9): 4030-4051, 2018 05 10.
Article in English | MEDLINE | ID: mdl-29648825

ABSTRACT

The use of an interleukin ß antibody is currently being investigated in the clinic for the treatment of acne, a dermatological disorder affecting 650M persons globally. Inhibiting the protease responsible for the cleavage of inactive pro-IL1ß into active IL-1ß, caspase-1, could be an alternative small molecule approach. This report describes the discovery of uracil 20, a potent (38 nM in THP1 cells assay) caspase-1 inhibitor for the topical treatment of inflammatory acne. The uracil series was designed according to a published caspase-1 pharmacophore model involving a reactive warhead in P1 for covalent reversible inhibition and an aryl moiety in P4 for selectivity against the apoptotic caspases. Reversibility was assessed in an enzymatic dilution assay or by using different substrate concentrations. In addition to classical structure-activity-relationship exploration, topical administration challenges such as phototoxicity, organic and aqueous solubility, chemical stability in solution, and skin metabolic stability are discussed and successfully resolved.


Subject(s)
Acne Vulgaris/drug therapy , Caspase 1/metabolism , Caspase Inhibitors/administration & dosage , Caspase Inhibitors/pharmacology , Drug Design , Acne Vulgaris/enzymology , Administration, Topical , Animals , Caspase 1/chemistry , Caspase Inhibitors/pharmacokinetics , Caspase Inhibitors/therapeutic use , Cell Line , Humans , Mice , Models, Molecular , Protein Conformation , Solvents/chemistry , Tissue Distribution
5.
J Med Chem ; 61(7): 3231-3236, 2018 04 12.
Article in English | MEDLINE | ID: mdl-29547279

ABSTRACT

Phototoxicity occurs when UV irradiation causes otherwise benign compounds to become irritant, sensitizers, or even genotoxic. This toxicity is particularly a concern after topical application and in dermatological programs where skin irritation can be incompatible with the desired therapeutic outcome. This brief article establishes that the intrinsic property forecast index (iPFI) can be used to evaluate the probability of a compound being phototoxic and gives medicinal chemists a practical tool to handle this liability.


Subject(s)
Algorithms , Chemistry, Pharmaceutical/methods , Dermatitis, Phototoxic , Heuristics , 3T3 Cells , Animals , Electrons , Forecasting , Humans , Keratinocytes/drug effects , Keratinocytes/radiation effects , Mice , Photosensitizing Agents , Structure-Activity Relationship , Ultraviolet Rays
6.
ChemMedChem ; 13(4): 321-337, 2018 02 20.
Article in English | MEDLINE | ID: mdl-29327456

ABSTRACT

With possible implications in multiple autoimmune diseases, the retinoic acid receptor-related orphan receptor RORγ has become a sought-after target in the pharmaceutical industry. Herein are described the efforts to identify a potent RORγ inverse agonist compatible with topical application for the treatment of skin diseases. These efforts culminated in the discovery of N-(2,4-dimethylphenyl)-N-isobutyl-2-oxo-1-[(tetrahydro-2H-pyran-4-yl)methyl]-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide (CD12681), a potent inverse agonist with in vivo activity in an IL-23-induced mouse skin inflammation model.


Subject(s)
Nuclear Receptor Subfamily 1, Group F, Member 3/agonists , Psoriasis/drug therapy , Sulfonamides/chemistry , Administration, Topical , Animals , Disease Models, Animal , Drug Evaluation, Preclinical , Drug Inverse Agonism , Humans , Inhibitory Concentration 50 , Interleukin-17/metabolism , Interleukin-23/pharmacology , Keratinocytes/cytology , Keratinocytes/drug effects , Keratinocytes/metabolism , Mice , Mice, Inbred BALB C , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Psoriasis/pathology , Skin Diseases/chemically induced , Skin Diseases/drug therapy , Skin Diseases/pathology , Structure-Activity Relationship , Sulfonamides/metabolism , Sulfonamides/therapeutic use , Th17 Cells/cytology , Th17 Cells/drug effects , Th17 Cells/metabolism
7.
Bioorg Med Chem Lett ; 27(24): 5373-5377, 2017 12 15.
Article in English | MEDLINE | ID: mdl-29157864

ABSTRACT

Virtual fragmentation of a library of 12,000 compounds inspired by natural products led to a dataset of 153,000 fragments that was used as a source to identify effective P2-P3 scaffold replacement solutions for peptidic Caspase-1 inhibitors. Our strategy led to the identification of an original 2-azabicyclo-octane scaffold (2-ABO) that was further elaborated into the potent Caspase-1 inhibitor CD10847 (IC50 = 17 nM). The crystal structure of Caspase-1 in complex with CD10847 was obtained, and its binding mode was shown to be similar to the one predicted by docking and in good agreement with other known inhibitors.


Subject(s)
4-Butyrolactone/analogs & derivatives , Caspase 1/chemistry , Caspase Inhibitors/chemistry , Dipeptides/chemistry , 4-Butyrolactone/chemical synthesis , 4-Butyrolactone/chemistry , 4-Butyrolactone/metabolism , Azabicyclo Compounds/chemistry , Azabicyclo Compounds/metabolism , Binding Sites , Biological Products/chemistry , Biological Products/metabolism , Caspase 1/metabolism , Caspase Inhibitors/metabolism , Crystallography, X-Ray , Dipeptides/chemical synthesis , Dipeptides/metabolism , Hydrogen Bonding , Inhibitory Concentration 50 , Molecular Conformation , Molecular Docking Simulation , Protein Structure, Tertiary
8.
Bioorg Med Chem Lett ; 21(14): 4366-8, 2011 Jul 15.
Article in English | MEDLINE | ID: mdl-21689930

ABSTRACT

Our series of competitive antagonists against the G-protein coupled receptor P2Y(14) were found to be highly shifted in the presence of serum (>99% protein bound). A binding assay using 2% human serum albumin (HSA) was developed to guide further SAR studies and led to the identification of the zwitterion 2, which is substantially less shifted (18-fold) than our previous lead compound 1 (323-fold). However, as the bioavailability of 2 was low, a library of ester pro-drugs was prepared (7a-7j) and assessed in vitro. The most interesting candidates were then profiled in vivo and led to the identification of the pro-drug 7j, which possesses a substantially improved pharmacokinetic profile.


Subject(s)
Prodrugs/chemistry , Purinergic P2 Receptor Antagonists/chemistry , Receptors, Purinergic P2/chemistry , Biological Availability , Humans , Microsomes, Liver/metabolism , Prodrugs/chemical synthesis , Prodrugs/pharmacokinetics , Protein Binding , Purinergic P2 Receptor Antagonists/chemical synthesis , Purinergic P2 Receptor Antagonists/pharmacokinetics , Receptors, Purinergic P2/metabolism , Structure-Activity Relationship
9.
Bioorg Med Chem Lett ; 21(10): 2836-9, 2011 May 15.
Article in English | MEDLINE | ID: mdl-21507640

ABSTRACT

A weak, UDP-competitive antagonist of the pyrimidinergic receptor P2RY(14) with a naphthoic acid core was identified through high-throughput screening. Optimization provided compounds with improved potency but poor pharmacokinetics. Acylglucuronidation was determined to be the major route of metabolism. Increasing the electron-withdrawing nature of the substituents markedly reduced glucuronidation and improved the pharmacokinetic profile. Additional optimization led to the identification of compound 38 which is an 8 nM UDP-competitive antagonist of P2Y(14) with a good pharmacokinetic profile.


Subject(s)
Carboxylic Acids/chemical synthesis , Naphthalenes/chemical synthesis , Purinergic P2 Receptor Antagonists/chemical synthesis , Receptors, Purinergic P2 , Uridine Diphosphate , Animals , Binding, Competitive , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacokinetics , Carboxylic Acids/pharmacology , Mice , Molecular Structure , Naphthalenes/chemistry , Naphthalenes/pharmacokinetics , Naphthalenes/pharmacology , Pan troglodytes , Protein Binding/drug effects , Purinergic P2 Receptor Antagonists/chemistry , Purinergic P2 Receptor Antagonists/pharmacokinetics , Purinergic P2 Receptor Antagonists/pharmacology , Receptors, Purinergic P2Y , Structure-Activity Relationship
10.
Biol Chem ; 391(12): 1469-73, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20868234

ABSTRACT

Renin is the first enzyme in the renin-angiotensin-aldosterone system which is the principal regulator of blood pressure and hydroelectrolyte balance. Previous studies suggest that cathepsin B is the activator of the prorenin zymogen. Here, we show no difference in plasma renin activity, or mean arterial blood pressure between wild-type and cathepsin B knockout mice. To account for potential gene compensation, a potent, selective, reversible cathepsin B inhibitor was developed to determine the role of cathepsin B on prorenin processing in rats. Pharmacological inhibition of cathepsin B in spontaneously hypertensive and double transgenic rats did not result in a reduction in renal mature renin protein levels or plasma renin activity. We conclude that cathepsin B does not play a significant role in this process in rodents.


Subject(s)
Cathepsin B/physiology , Renin/metabolism , Animals , Cathepsin B/antagonists & inhibitors , Cathepsin B/genetics , Enzyme Inhibitors/pharmacology , Hypertension/genetics , Hypertension/metabolism , Mice , Mice, Knockout , Rats , Rats, Transgenic
11.
J Card Surg ; 23(2): 163-4, 2008.
Article in English | MEDLINE | ID: mdl-18304134

ABSTRACT

The patient, who had undergone a complete cure of a tetralogy of Fallot 25 years previously, was discovered to have an ascending aorta aneurysm on echography. Bentall's procedure was carried-out, using a modified indirect coronary artery transplantation based on the Cabrol technique. As reported in the literature complications are mainly right sided and less frequently occur on the left side in this disease. Including the hypothesis of the overload volume which may provoke aortic root dilation, there is also an intrinsic pathology of the media which could often be related to embryogenesis abnormalities, i.e., abnormal migration of cardiac neural crest cells which may explain this condition.


Subject(s)
Aorta/surgery , Aortic Aneurysm, Thoracic/etiology , Cardiac Surgical Procedures/adverse effects , Tetralogy of Fallot/surgery , Adrenergic beta-Antagonists/therapeutic use , Adult , Aorta/pathology , Aortic Aneurysm, Thoracic/diagnosis , Aortic Aneurysm, Thoracic/diagnostic imaging , Coronary Vessels/surgery , Female , Humans , Risk Factors , Time Factors , Ultrasonography
12.
J Am Chem Soc ; 127(38): 13140-1, 2005 Sep 28.
Article in English | MEDLINE | ID: mdl-16173730

ABSTRACT

The highly diastereoselective zinco-cyclopropanation of chiral allylic alcohols using gem-dizinc carbenoids is described. The reaction produces three contiguous stereogenic centers, and the resulting chiral cyclopropylzinc derivatives can be trapped with electrophiles with retention of configuration. Simple functional group manipulations lead to the efficient synthesis of orthogonally protected 1,2,3-substituted cyclopropane derivatives.


Subject(s)
Cyclopropanes/chemistry , Organometallic Compounds/chemical synthesis , Propanols/chemistry , Zinc/chemistry , Crystallography, X-Ray , Cyclization , Cyclopropanes/chemical synthesis , Models, Molecular , Molecular Conformation , Organometallic Compounds/chemistry , Propanols/chemical synthesis , Stereoisomerism
13.
Org Lett ; 7(13): 2699-701, 2005 Jun 23.
Article in English | MEDLINE | ID: mdl-15957925

ABSTRACT

[reaction: see text] A total synthesis of the salinosporamide analogue 3 is described that starts with the novel cyclization 4 --> 5.


Subject(s)
Lactones/chemical synthesis , Pyrroles/chemical synthesis , Catalysis , Cyclization , Lactones/chemistry , Lactones/pharmacology , Molecular Structure , Pyrroles/chemistry , Pyrroles/pharmacology , Stereoisomerism
14.
Org Lett ; 7(13): 2703-5, 2005 Jun 23.
Article in English | MEDLINE | ID: mdl-15957926

ABSTRACT

[reaction: see text] Syntheses of two novel omuralide derivatives are described.


Subject(s)
Lactones/chemical synthesis , Catalysis , Lactones/chemistry , Molecular Structure , Stereoisomerism
15.
J Am Chem Soc ; 127(25): 8974-6, 2005 Jun 29.
Article in English | MEDLINE | ID: mdl-15969573

ABSTRACT

A short and highly stereocontrolled synthesis of the potent proteasome inhibitor 3 from the (S)-threonine-derived oxazoline 4 has been developed. The synthetic sequence is summarized in Scheme 1. Aldol coupling of the zinc enolate of 4 with isobutyraldehyde and subsequent silylation provided the TBS ether 5 diastereoselectively (10:1). Reductive cleavage of the oxazoline ring of 5 followed by Swern oxidation of the resulting amino alcohol afforded amino ketone 6, converted further by N-acylation to the acrylamide 7, whose structure was confirmed by X-ray crystallographic analysis. Acrylamide 7 was cyclized to 8 by a novel application of the Kulinkovich Ti(II)-cyclopentene complex. Silylation of 8 to 9 and radical cyclization at low temperature produced the bicyclic lactam 10 with complete control of all stereocenters. Hydroxy desilylation and N-deprotection of 10 gave the dihydroxy ester 11, which was converted to 3 by a novel three-step sequence: (1) demethylation with [Me2AlTeMe]2, (2) combined beta-lactonization and chlorination, and (3) desilylation to effect cleavage of the TBS ether.


Subject(s)
Enzyme Inhibitors/pharmacology , Lactones/chemical synthesis , Lactones/pharmacology , Proteasome Inhibitors , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Lactones/chemistry , Molecular Conformation , Pyrroles/chemistry , Stereoisomerism
16.
Photochem Photobiol Sci ; 2(11): 1052-5, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14690213

ABSTRACT

Moderate to high enantiomeric excesses for the cis and trans olefinic products of a Norrish type II cleavage reaction have been obtained for the first time through the use of the solid-state ionic chiral auxiliary approach.

17.
J Am Chem Soc ; 124(3): 386-7, 2002 Jan 23.
Article in English | MEDLINE | ID: mdl-11792203

ABSTRACT

Significant amounts of novel gem-dizinc carbenoids (RZnCHIZnR) are formed when diethylzinc is mixed with iodoform in CH2Cl2 at 0 degrees C. This reagent was shown to be effective in the cyclopropanation of butenediol derivatives to generate a cyclopropylzinc intermediate that could be trapped with a variety of electrophiles. 1,2,3-Substituted cyclopropane derivatives are formed with excellent diastereoselectivities by using this simple procedure.


Subject(s)
Cyclopropanes/chemical synthesis , Stereoisomerism
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