Changes in Public Response Associated With Various COVID-19 Restrictions in Ontario, Canada: Observational Infoveillance Study Using Social Media Time Series Data.

Background: News media coverage of antimask protests, COVID-19 conspiracies, and pandemic politicization has overemphasized extreme views but has done little to represent views of the general public. Investigating the public's response to various pandemic restrictions can provide a more balanced assessment of current views, allowing policy makers to craft better public health messages in anticipation of poor reactions to controversial restrictions.

Objective: Using data from social media, this infoveillance study aims to understand the changes in public opinion associated with the implementation of COVID-19 restrictions (eg, business and school closures, regional lockdown differences, and additional public health restrictions, such as social distancing and masking).

N-(arylacetyl)-biphenylalanines as potent VLA-4 antagonists.

A series of potent N-(aralkyl-, arylcycloalkyl-, and heteroaryl-acyl)-4-biphenylalanine VLA-4 antagonists was prepared by rapid analogue methods using solid-phase chemistry. Further optimization led to several highly potent compounds (IC(50) <1 nM). Evaluation of rat pharmacokinetic revealed generally high clearance.

The discovery of acylated beta-amino acids as potent and orally bioavailable VLA-4 antagonists.

Acylated beta-amino acids are described as potent, specific and orally bioavailable antagonists of VLA-4. The initial lead was identified from a combinatorial library. Subsequent optimization using a traditional medicinal chemistry approach led to significant improvement in potency (up to 8-fold) while maintaining good pharmacokinetic properties.

The discovery of sulfonylated dipeptides as potent VLA-4 antagonists.

Directed screening of a carboxylic acid-containing combinatorial library led to the discovery of potent inhibitors of the integrin VLA-4. Subsequent optimization by solid-phase synthesis afforded a series of sulfonylated dipeptide inhibitors with structural components that when combined in a single hybrid molecule gave a sub-nanomolar inhibitor as a lead for medicinal chemistry. Preliminary metabolic studies led to the discovery of substituted biphenyl derivatives with low picomolar activities.

Substituted 2-aminopyridines as inhibitors of nitric oxide synthases.

A series of substituted 2-aminopyridines was prepared and evaluated as inhibitors of human nitric oxide synthases (NOS). 4,6-Disubstitution enhanced both potency and specificity for the inducible NOS with the most potent compound having an IC50 of 28 nM.

Structural requirements for human inducible nitric oxide synthase substrates and substrate analogue inhibitors.

Inducible nitric oxide synthase (iNOS; EC 1.14.13.

Inhibition of stromelysin-1 (MMP-3) by P1'-biphenylylethyl carboxyalkyl dipeptides.

Carboxyalkyl peptides containing a biphenylylethyl group at the P1' position were found to be potent inhibitors of stromelysin-1 (MMP-3) and gelatinase A (MMP-2), in the range of 10-50 nM, but poor inhibitors of collagenase (MMP-1). Combination of a biphenylylethyl moiety at P1', a tert-butyl group at P2', and a methyl group at P3' produced orally bioavailable inhibitors as measured by an in vivo model of MMP-3 degradation of radiolabeled transferrin in the mouse pleural cavity. The X-ray structure of a complex of a P1-biphenyl inhibitor and the catalytic domain of MMP-3 is described.

Inhibition of matrix metalloproteinases by N-carboxyalkyl peptides.

An extensive study of the requirements for effective binding of N-carboxyalkyl peptides to human stromelysin, collagenase, and to a lesser extent, gelatinase A has been investigated. These efforts afforded inhibitors generally in the 100-400 nM range for these matrix metalloproteinases. The most significant increase in potency was obtained with the introduction of a beta-phenylethyl group at the P1' position, suggesting a small hydrophobic channel into the S1' subsite of stromelysin.

Substituted 4,6-diaminoquinolines as inhibitors of C5a receptor binding.

The anaphylatoxin C5a is implicated in a number of inflammatory diseases. It is a highly cationic protein with 13 of 74 amino acids being either arginine or lysine. A search focusing on positively charged molecules, particularly amine-containing functionalities, led to the discovery of substituted 4,6-diaminoquinolines 1 [N,N'-bis(4-amino-2-methyl-6-quinolyl)urea] and 7 [6-N-(2-chlorocinnamoyl)-4,6-diamino-2-methylquinoline] as inhibitors of C5a receptor binding.

Conformation of MeAla6-cyclosporin A by NMR. Relationship of sidechain orientation of the MeBmt-1, MeLeu-9, and MeLeu-10 residues to immunosuppressive activity.

MeAla6-cyclosporin A (MeAla6-CsA) is a unique CsA analog that shows weak immunosuppressive activity and yet binds strongly to the proposed cytosolic protein receptor, cyclophilin (CyP). Preliminary 1H NMR data showed significant chemical shift differences between spectra of MeAla6-CsA and CsA, suggesting different preferred conformations. A more detailed study, however, revealed that the backbone conformations of the two molecules are essentially identical, and that the differences can be accounted for, principally, by the sidechain motions of the MeBmt-1, MeLeu-9, and -10 residues.

Is cyclophilin involved in the immunosuppressive and nephrotoxic mechanism of action of cyclosporin A?

In this report we have approached two questions relating to the mechanism of action of cyclosporin A (CsA). First, we address whether the major cytosolic protein for CsA, cyclophilin, is directly involved in mediating the immunosuppressive activity of this drug, and, in particular, whether inhibition of this protein's peptidyl-prolyl cis-trans isomerase (PPIase) activity results in inhibition of murine T cell activation. Second, we ask whether the nephrotoxicity observed with CsA is related to inhibition of PPIase-dependent pathways in cells other than lymphocytes.

Unexpected up-regulation of gene expression by cyclosporin A and FK-506 in a T-cell lymphoma: both immunosuppressants augment Ly-6E antigen induction by interferon-gamma in the presence of ionomycin.

Cyclosporin A (CsA) and FK-506 inhibit lymphokine gene activation in T-cells. In the present study, we investigated the effects of these immunosuppressants on the regulation of a non-lymphokine molecule, the Ly-6E surface antigen, in the YAC-1 T-cell lymphoma. These cells do not normally express Ly-6E mRNA or Ly-6E surface molecules but are induced to do so upon treatment with IFN-gamma.

A study of the correlation between cyclophilin binding and in vitro immunosuppressive activity of cyclosporine A and analogues.

In order to establish whether CyP is the pharmacologically relevant CsA receptor, the CyP binding v immunosuppressive activity was measured for an extensive, structurally varied group of CsA analogues. Overall, CyP binding was found to parallel immunosuppressive activity. Other than MeAla6-CsA, the few exceptions to the correlation could be ascribed to cellular metabolism.

Pharmacology of the dual inhibitor of cyclooxygenase and 5-lipoxygenase 3-hydroxy-5-trifluoromethyl-N-(2-(2-thienyl)-2-phenyl-ethenyl)-benzo (b)thiophene-2-carboxamide.

3-Hydroxy-5-trifluoromethyl-N-(2-(2-thienyl)-2-phenyl-ethenyl)- benzo (b) thiophene-2-carboxamide (L-652,343) is an inhibitor of cyclooxygenase and 5-lipoxygenase in vitro and inhibits the synthesis of the products of both these pathways in whole cells. L-652,343 is an inhibitor of the acute edema induced by carrageenan in vivo and is active topically in suppressing arachidonic acid induced inflammation in the skin. The compound is an effective inhibitor of the chronic inflammation of adjuvant and type II collagen induced polyarthritis.

Synthesis and immunoadjuvant activities of 2-acetamido-5-O-acetyl-6-O-acyl-2-deoxy-3-O-[(R)-2-propionyl-L-alanyl-D- isoglutamine]-D-glucofuranoses as potential prodrug forms of 6-O-Acyl Derivatives of N-acetylmuramyl dipeptide.

2-Acetamido-5-O-acetyl-6-O-acyl-2-deoxy-3-O-[(R)-2-propionyl-L-alanyl-D- isoglutamine]-D-glucofuranoses, designed as prodrug forms of the corresponding immunoadjuvant-active 6-O-acyl derivatives of N-acetylmuramyl dipeptide (MDP), were synthesized from benzyl 2-acetamido-2-deoxy-5, 6-O-isopropylidene-beta-D-glucofuranoside and found, when administered to mice in an aqueous medium, to elevate antibody production against bovine serum albumin. The 5,6-di-O-acetyl derivative 8 exhibited activity similar to that of MDP at 50 micrograms/dose. The antibody titer measured for the 5-O-acetyl-6-O-stearoyl compound 9 was comparable to that obtained with 6-O-stearoyl-MDP at 50 micrograms, and both compounds were more active than MDP at 5 micrograms.

Synthesis of 2-methyl-[2-acetamido-4-O-acetyl-6-O-benzyl-3-O-(2-butenyl)-1,2-dideoxy-alpha-D -glucopyrano]-[2,1-d]-2-oxazoline, a versatile intermediate for the synthesis of complex oligosaccharides of bacterial cell-wall, human milk, and blood-group substances.

2-Methyl-[2-acetamido-4-O-acetyl-6-O-benzyl-3-O-(2-butenyl)-1,2-dideoxy-alpha-D-glucopyrano]-[2,1-d]-2-oxazoline (2), a glycosylating agent in which the three hydroxyl groups are blocked with protecting groups of differing "persistence", is of utility in the synthesis of oligosaccharides containing highly branched 2-acetamido-2-deoxy-D-glucosyl residues, and it was synthesized in a ten-step sequence from 2-acetamido-2-deoxy-D-glucose via allyl 2-acetamido-4,6-O-benzylidene-2-deoxy-beta-D-glucopyranoside (3). Alkylation of 3 with 2-butenyl (crotyl) bromide, hydrolysis of the benzylidene acetal group, benzylation of the 6-hydroxyl group, and acetylation of the 4-hydroxyl group afforded allyl 2-acetamido-4-O-acetyl-6-O-benzyl-3-O-(2-butenyl)-2-deoxy-beta-D-glucopyranoside(10). Treatment of 10 with chlorotris(tri-phenylphosphine)rhodium(I) gave mainly the corresponding 1-propenyl beta-glycoside, which was converted into oxazoline 2 by the action of mercuric chloride-mercuric oxide in acetonitrile.

Insulin-like, and insulin-antagonistic, carbohydrate derivatives. The synthesis of aryl and aralkyl D-mannopyranosides and 1-thio-D-mannopyranosides.

A number of novel, aryl and aralkyl D-mannopyranosides and 1-thio-D-mannopyranosides were synthesized for evaluation of insulin-like and insulin-antagonistic properties. The substituted-phenyl alpha-D-mannopyranosides were prepared by the general procedure of Helferich and Schmitz-Hillebrecht, the substituted-phenyl 1-thio-alpha-D-mannopyranosides by a method corresponding to the Michael synthesis of aromatic glycosides, and the aralkyl 1-thio-alpha-D-mannopyranosides by aralkylation of 2,3,4,6-tetra-O-acetyl-1-thio-alpha-D-mannopyranose (15) and subsequent O-deacetylation. Compound 15 was obtained by basic cleavage of the amidino group in 2-S-(tetra-O-acetyl-alpha-D-mannopyranosyl)-2-thiopseudourea hydrobromide, the product of the reaction of tetra-O-acetyl-alpha-D-mannosyl bromide with thiourea.

Structure-activity relationships of aminoalkyl and -aryl glycosides having insulin-like activity.

A number of alkyl, aryl, and aralkyl glycosides (mono- and disaccharides) substituted in the aglycon with a primary amino group have been found to exert insulin-like activity on rat adipocytes in vitro. Systematic variations in the saccharide configuration, glycosidic linkage, aglycon moiety, and sugar substitution pattern were investigated to delineate structure-activity relationships. A high degree of structural specificity was observed.