Discovery of a novel series of selective macrocyclic PKCTheta inhibitors.

A series of macrocyclic PKCθ inhibitors based on a 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hinge binder has been studied. Different aromatic and heteroaromatic substituents have been explored in order to optimize potency, isoform selectivity as well as DMPK properties. The importance of the length of the macrocyclic linker has also been analyzed.

Frailty and Persistent Pain in Oncological Patients Undergoing Rehabilitation.

Objectives: Pain is one of the most common symptoms among oncological patients and has a strong negative impact on quality of life. The aim of this study is to assess if frailty and polypharmacy are associated with persistent pain in oncological patients undergoing rehabilitation.

Design: Observational, prospective, longitudinal study.

Tale of two countries: attitudes towards older persons in Italy and Israel during the COVID-19 pandemic as seen through the looking-glass of the media.

The COVID-19 pandemic has exposed the many challenges and difficulties of healthcare systems caring for older frail people. This public health crisis has indeed jeopardised the concept of the welfare state, in particular the right of older people to uncompromised healthcare. Together with the clinical challenges facing the geriatric patient and the organisational difficulties of the healthcare systems, sociocultural factors may have also played a substantial role in the strategies that countries have applied in coping with the pandemic.

Structure-Based Optimization and Discovery of M3258, a Specific Inhibitor of the Immunoproteasome Subunit LMP7 (β5i).

Proteasomes are broadly expressed key components of the ubiquitin-dependent protein degradation pathway containing catalytically active subunits (β1, β2, and β5). LMP7 (β5i) is a subunit of the immunoproteasome, an inducible isoform that is predominantly expressed in hematopoietic cells. Clinically effective pan-proteasome inhibitors for the treatment of multiple myeloma (MM) nonselectively target LMP7 and other subunits of the constitutive proteasome and immunoproteasome with comparable potency, which can limit the therapeutic applicability of these drugs.

Frailty and Geriatric Medicine During the Pandemic.

The term in the era of coronavirus disease 2019 (COVID-19) has a manifold implication. The vast majority of the countries worldwide being hit by the pandemic have shown the frailty of their health and social care systems. Although the surprise factor could somehow justify the unpreparedness experienced during the first wave, the second wave still led to significant difficulties almost everywhere.

SARCOPENIA IN PRIMARY CARE: SCREENING, DIAGNOSIS, MANAGEMENT.

Detection of sarcopenia in primary care is a first and essential step in community-dwelling older adults before implementing preventive interventions against the onset of disabling conditions. In fact, leaving this condition undiagnosed and untreated can impact on the individual's quality of life and function, as well as on healthcare costs. This article summarizes the many instruments today available for promoting an earlier and prompter detection of sarcopenia in primary care, combining insights about its clinical management.

Inhibition of Tryptophan-Dioxygenase Activity Increases the Antitumor Efficacy of Immune Checkpoint Inhibitors.

Tryptophan 2,3-dioxygenase (TDO) is an enzyme that degrades tryptophan into kynurenine and thereby induces immunosuppression. Like indoleamine 2,3-dioxygenase (IDO1), TDO is considered as a relevant drug target to improve the efficacy of cancer immunotherapy. However, its role in various immunotherapy settings has not been fully characterized.

Characterization of the Selective Indoleamine 2,3-Dioxygenase-1 (IDO1) Catalytic Inhibitor EOS200271/PF-06840003 Supports IDO1 as a Critical Resistance Mechanism to PD-(L)1 Blockade Therapy.

Tumors use indoleamine 2,3-dioxygenase-1 (IDO1) as a major mechanism to induce an immunosuppressive microenvironment. IDO1 expression is upregulated in many cancers and considered to be a resistance mechanism to immune checkpoint therapies. IDO1 is induced in response to inflammatory stimuli such as IFNγ and promotes immune tolerance by depleting tryptophan and producing tryptophan catabolites, including kynurenine, in the tumor microenvironment.

Discovery of a Novel and Selective Indoleamine 2,3-Dioxygenase (IDO-1) Inhibitor 3-(5-Fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (EOS200271/PF-06840003) and Its Characterization as a Potential Clinical Candidate.

Tumors use tryptophan-catabolizing enzymes such as indoleamine 2,3-dioxygenase (IDO-1) to induce an immunosuppressive environment. IDO-1 is induced in response to inflammatory stimuli and promotes immune tolerance through effector T-cell anergy and enhanced Treg function. As such, IDO-1 is a nexus for the induction of a key immunosuppressive mechanism and represents an important immunotherapeutic target in oncology.

Pharmacophore-based design of novel oxadiazoles as selective sphingosine-1-phosphate (S1P) receptor agonists with in vivo efficacy.

Sphingosine-1-phosphate (S1P) receptor agonists have shown promise as therapeutic agents for multiple sclerosis (MS) due to their regulatory roles within the immune, central nervous system, and cardiovascular system. Here, the design and optimization of novel [1,2,4]oxadiazole derivatives as selective S1P receptor agonists are described. The structure-activity relationship exploration was carried out on the three dominant segments of the series: modification of the polar head group (P), replacement of the oxadiazole linker (L) with different five-membered heterocycles, and the use of diverse 2,2'-disubstituted biphenyl moieties as the hydrophobic tail (H).

Discovery of a Novel Series of CRTH2 (DP2) Receptor Antagonists Devoid of Carboxylic Acids.

Antagonism of the CRTH2 receptor represents a very attractive target for a variety of allergic diseases. Most CRTH2 antagonists known to date possess a carboxylic acid moiety, which is essential for binding. However, potential acid metabolites O-acyl glucuronides might be linked to idiosynchratic toxicity in humans.

Discovery of potent, selective, and orally bioavailable alkynylphenoxyacetic acid CRTH2 (DP2) receptor antagonists for the treatment of allergic inflammatory diseases.

New phenoxyacetic acid antagonists of CRTH2 are described. Following the discovery of a hit compound by a focused screening, high protein binding was identified as its main weakness. Optimization aimed at reducing serum protein binding led to the identification of several compounds that showed not only excellent affinities for the receptor (41 compounds with K(i) < 10 nM) but also excellent potencies in a human whole blood assay (IC(50) < 100 nM; PGD2-induced eosinophil shape change).

Optimization of the Central Core of Indolinone-Acetic Acid-Based CRTH2 (DP2) Receptor Antagonists.

New spiroindolinone antagonists of CRTH2 are described. Following identification of insufficient stability in human plasma as an important liability of the lead compounds, replacement of the spirosuccinimide core with a spirohydantoin or spiropyrrolidinone structure has yielded a compound that is fully stable in human plasma and with good potency in a human whole blood assay (IC50 = 69 nM) but shows a much lower oral bioavailability (6-9% in rodents) than the earlier compounds. Successive optimization aimed at restoring an acceptable oral bioavailability has yielded compound (S)-17a, which exhibits both stability in human plasma and a good oral bioavailability in rat (37%) and mouse (39%).

Novel application of α-azido aldehydes in multicomponent reactions: synthesis of triazolo-fused dihydrooxazinones via a Passerini reaction-dipolar cycloaddition strategy.

α-Azido aldehydes can be employed in Passerini reactions with isocyanides and various propiolic acids to afford the three-component adducts in moderate to good yields. These compounds undergo a straightforward azide-alkyne dipolar cycloaddition to furnish triazolo-fused dihydrooxazinones.

Discovery of a novel series of CXCR3 antagonists.

The discovery of a novel series of CXCR3 antagonists is described. Starting from an HTS positive, iterative optimization gave potent compounds (IC(50) 15 nM in a chemotaxis assay). The strategy employed to improve the metabolic stability of these derivatives is described.

Discovery of a novel series of potent S1P1 agonists.

The discovery of a novel series of S1P1 agonists is described. Starting from a micromolar HTS positive, iterative optimization gave rise to several single-digit nanomolar S1P1 agonists. The compounds were able to induce internalization of the S1P1 receptor, and a selected compound was shown to be able to induce lymphopenia in mice after oral dosing.

Microwave-assisted ester formation using O-alkylisoureas: a convenient method for the synthesis of esters with inversion of configuration.

The formation of carboxylic esters via reaction of carboxylic acids with O-alkylisoureas proceeds in excellent yields with very short reaction times when conducted in a monomode microwave synthesizer. Efficient processes were developed using preformed or commercially available isoureas derived from primary and secondary alcohols, with a reaction time of only 5 min or less. It was demonstrated that under these microwave conditions, ester formation proceeded in good yields with clean inversion of configuration where appropriate.

Discovery of a new class of potent, selective, and orally bioavailable CRTH2 (DP2) receptor antagonists for the treatment of allergic inflammatory diseases.

A novel chemical class of potent chemoattractant receptor-homologous expressed on Th2 lymphocytes (CRTH2 or DP2) antagonists is reported. An initial and moderately potent spiro-indolinone compound ( 5) was found during a high-throughput screening campaign. Structure-activity relationship (SAR) investigation around the carboxylic acid group revealed that changes in this part of the molecule could lead to a reversal of functional activity, yielding weakly potent agonists.

A practical synthesis of a high-loading solid-supported IBX amide for the oxidation of alcohols.

A straightforward three-step synthesis of a solid-supported IBX amide resin was achieved using inexpensive and commercially available 2-iodobenzoic acid chloride and Merrifield resin. A high apparent loading of 0.63 mmol g(-1) was obtained.

A straightforward, one-pot protocol for the preparation of libraries of 2-oxazolines.

A practical protocol for the parallel synthesis of 2-oxazolines using polymer-supported reagents is described. Polymer-supported Mukaiyama reagent is used to couple a carboxylic acid with an amino alcohol, giving a beta-hydroxyamide, which is then cyclized in situ using either polymer-supported sulfonyl chloride resin or polymer-bound 2-fluoropyridinium triflate. Both 2,4-disubstituted and 2,4,5-trisubstituted 2-oxazolines are obtained in high yields and excellent purities after a simple resin filtration and solvent evaporation routine.

Polymer-supported Mukaiyama reagent: a useful coupling reagent for the synthesis of esters and amides.

Polymer-supported N-alkyl-2-chloro pyridinium triflate was synthesized in one step from Wang resin. This reagent proved to be a very effective coupling reagent for the synthesis of esters or amides from carboxylic acids and alcohols or amines (primary and secondary). [reaction: see text]

Polymer-supported O-alkylisoureas: useful reagents for the O-alkylation of carboxylic acids.

Polymer-supported O-alkylisoureas were prepared by reaction of an alcohol with a polymer-supported carbodiimide under copper(II) catalysis. These reagents were used to transform carboxylic acids into the corresponding methyl, benzyl, allyl, and p-nitrobenzyl esters in a highly chemoselective manner in high yields and in very high purity after simple resin filtration and solvent evaporation. The reactions could be carried out using both conventional or microwave heating, with reaction times as short as 3-5 min in the latter case, without compromising yield, purity, or chemoselectivity.

Microwaves, supported-reagents and parallel synthesis: isocyanide and ester synthesis.

The benefits of microwave irradiation are described for a number of important reactions such as amid and ester formation and dehydration of formamide to the corresponding isonitriles. Not only were reaction times dramatically reduced but the transformations were less prone to side reactions and decomposition.

Polymer-supported o-benzyl and o-allylisoureas: convenient preparation and use in ester synthesis from carboxylic acids.

[reaction: see text] Polymer-supported O-methyl, O-benzyl, and O-allyl-isoureas were prepared by copper(II)-catalyzed reaction of polymer-supported carbodiimide with the corresponding alcohols. These polymer-supported reagents were successfully employed to convert a series of carboxylic acids to methyl, benzyl, or allyl esters, in good yields. The products were obtained with high purity (>95% by NMR) after a simple resin filtration-solvent evaporation sequence.