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BackgroundPatients with autoimmune systemic diseases (ASDs) can be counted among frail populations as regards the predisposition to COVID-19 due to the frequent visceral organ involvement and comorbidities, as well as the ongoing immunomodulating treatments.ObjectivesOur long-term multicenter telephone survey prospectively investigated the prevalence, prognostic factors, and outcomes of COVID-19 in Italian ASD patients during the first 3 pandemic waves.MethodsA large series of 3,918 ASD patients (815 M, 3103 F; mean age 59±12SD years) was consecutively recruited at the 36 referral centers of COVID-19 & ASD Italian Study Group. In particular, ASD series encompassed the following conditions: rheumatoid arthritis (n: 981), psoriatic arthritis (n: 471), ankylosing spondylitis (n: 159), systemic sclerosis (n: 1,738), systemic lupus (172), systemic vasculitis (n: 219), and a miscellany of other ASDs (n: 178). The development of COVID-19 was recorded by means of telephone survey using standardized symptom-assessment questionnaire (1).ResultsA significantly increased prevalence of COVID-19 (8.37% vs 6.49%; pInterestingly, a significantly higher COVID-19-related death rate was observed in systemic sclerosis patients compared to the Italian general population (6.29% vs 2.95%; p=0.018). Other adverse prognostic factors to develop COVID-19 were the patients’ older age, male gender, pre-existing ASD-related interstitial lung involvement, and chronic steroid treatment. Conversely, patients treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) showed a significantly lower prevalence of COVID-19 compared to those without (3.58% vs 46.99%; p=0.000), as well as the chronic administration of low dose aspirin in a subgroup of SSc patients (with 5.57% vs without 27.84%; p=0.000).ConclusionThe cumulative impact of COVID-19 on ASD patients after the first 3 pandemic waves revealed less severe than that observed during the first phase of pandemic (1), especially with regards to the death rate that was comparable to the Italian general population in spite of the increased prevalence of complicating COVID-19 in the same ASD series.Ongoing long-term treatments, mainly csDMARDs, might usefully contribute to generally positive outcomes of in this frail patients’ population.Of note, a significantly increased COVID-19-related mortality was recorded in only SSc patients’ subgroup, possibly favored by pre-existing lung fibrosis. Among different ASD, SSc deserves special attention, since it shares the main pathological alterations with COVID-19, namely the interstitial lung involvement and the endothelial injury responsible for diffuse microangiopathy.Besides SSc, the patients’ subgroups characterized by older age, chronic steroid treatment, pre-existing interstitial lung disease, and/or impaired COVID-19 vaccine response (1-3), may deserve well-designed prevention and management strategies.References[1]Ferri C, et al. Ann Rheum Dis. 2020 Oct 14 doi: 10.1136/annrheumdis-2020-219113.[2]Ferri C et al. J Autoimmun. 2021 Dec;125:102744. doi: 10.1016/j.jaut.2021.102744.[3]Visentini M et al. Ann Rheum Dis. 2021 Nov 24. doi: 10.1136/annrheumdis-2021-221248Disclosure of InterestsNone declared

Bis-aryl ureas have been disclosed previously as a potent class of Raf kinase inhibitors. Modifications in the amide portion led to an improvement in aqueous solubility, an important characteristic for an oral drug. Based on this finding, we hypothesize that this portion of the molecule is directed towards the solvent in Raf-1.

Procedures for solution phase parallel synthesis of new, small molecule cathepsin D inhibitors by the coupling of acyl chlorides, sulfonyl chlorides and carboxylic acids with nitrogen nucleophiles have been established using polymer-bound reagents to facilitate the chemistry and/or to efficiently scavenge the unreacted starting materials and reaction by-products. Silver(I) benzoate was used to facilitate the coupling of acyl chlorides with less reactive anilines. Compound 4 was identified as a sub-micromolar cathepsin D inhibitor (IC50=320 nM).

Cathepsin D, a lysosomal aspartyl protease, has been implicated in the pathology of Alzheimer's disease as well as breast and ovarian cancer. A weakly active cathepsin D inhibitor was identified by high throughput screening. Subsequent optimization led to the discovery of a new class of small molecule inhibitors througput screening. Subsequent optimization led to the discovery of a new class of small molecule inhibitors of this enzyme, culminating with the sulfonamide 13 (IC 50 = 250 nM).

Japanese medaka (Oryzias latipes) and channel catfish (Ictalurus punctatus) were investigated for carcinogenic response following a 28-day, 3X/wk pulse exposure to N-methyl- N'-nitro- N-nitrosoguanidine (MNNG). Five-wk-old medaka were exposed at concentrations of 0, 0.5, and 1.0 mg/L, and 5-mo-old catfish at concentrations of 0, 0.1, and 0.5 mg/L. In medaka, a total of 19 tumors including 2 branchioblastomas, 6 thyroid follicular adenomas and 1 adenocarcinoma, and 11 subcutaneous fibrosarcomas were observed in 16 of 96 MNNG-exposed fish. In catfish, a total of 37 tumors including 4 squamous cell carcinomas and 16 papillomas, 3 lipomas, 1 fibroma, 1 osteosarcoma, 4 branchioblastomas, 6 thymic epithelial tumors, and 2 generalized lymphosarcomas were observed in 34 of 172 MNNG-exposed fish. The induction of neoplasms in medaka was primarily in the gill, thyroid, and subcutis of the cervical and trunk regions, whereas in catfish skin, thymus, oro-pharynx, and hemopoietic tissues were also commonly affected. In both species, the neoplastic response was considered to be related to direct exposure of the tissues to MNNG. Some of these tumors have not been reported in the literature in either natural or experimental fish. The results also suggest species-specific differences in carcinogenic response following MNNG exposure.

Ring-constrained boropeptide thrombin inhibitors were designed using information from the X-ray crystal structure of 1 (3-Phenylpropionyl-Pro-boroLys-OH ·HCl) bound to thrombin. The constraints utilized cyclohexane and pyrrolidine rings to preorganize an aromatic ring in an orientation allowing optimum edge-to-face interaction with the tryptophan 215 side chain located in the S3 specificity pocket of thrombin.

A series of boropeptide thrombin inhibitors was prepared in which the P3 residues of 2 (Ac-( D )-Phe-Pro-boroLys-OH · HCl) and 3 (3-Phenylpropionyl-Pro-boroLys-OH · HCl) were replaced by conformationally-restricted, benzoic acid-derived residues 4 . The potent binding affinity of the resulting inhibitors such as 10 may be due in part to a unique mode of binding in the thrombin active site.

A number of analogs of the cognition enhancing agent DuP 996 were prepared by varying the core structure and pendant groups in an independent fashion. The SAR of 2-, 3-, and 4-pyridinylmethyl groups as pendant groups on selected cores was examined.

The synthesis and structure-activity relationship (SAR) studies of the effect of different polysubstitution patterns in the aromatic ring of 5-(acetamidomethyl)oxazolidinone antibacterials (I) on antibacterial activity are presented. Compounds I were prepared by the six-step synthesis described previously (Gregory, W. A.; et al. J. Med. Chem. [formula: see text] 1989, 32, 1673), electrophilic aromatic substitution reactions of 3-substituted compounds, and functional-group interchange reactions of 3,4-disubstituted compounds. Antibacterial evaluation of compounds I against Staphylococcus aureus and Enterococcus faecalis gave the following results. The 2,4- and 2,5-disubstituted derivatives have weak or no antibacterial activity. Antibacterial activities of 3,4-disubstituted compounds are comparable to those of the 4-monosubstituted analogues for small 3-substituents (smaller than Br), but decline rapidly for larger 3-substituents. 3,4-Annulated derivatives are comparable in activity to their open-chain analogues. 3,5-Disubstituted and 3,4,5- and 2,4,6-trisubstituted derivatives are devoid of antibacterial activity.

Inhibition of receptor tyrosine kinases (RTKs) such as vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs) has been validated by recently launched small molecules Sutent® and Nexavar®, both of which display activities against several angiogenesis-related RTKs. EphB4, a receptor tyrosine kinase (RTK) involved in the processes of embryogenesis and angiogenesis, has been shown to be aberrantly up regulated in many cancer types such as breast, lung, bladder and prostate. We propose that inhibition of EphB4 in addition to other validated RTKs would enhance the anti-angiogenic effect and ultimately result in more pronounced anti-cancer efficacy. Herein we report the discovery and SAR of a novel series of imidazo[1,2-a]pyrazine diarylureas that show nanomolar potency for the EphB4 receptor, in addition to potent activity against several other RTKs.

The synthesis and structure-activity relationship (SAR) studies of the effect of varying the "A" group in a series of 5-(acetamidomethyl)oxazolidonone antibacterials (2) are described. Compounds 2 were principally prepared either by the six-step synthesis described previously (J. Med. Chem. 1989, 32, 1673) or by elaboration of the synthetic intermediate 2 (A = H) via electrophilic aromatic substitution or elaboration of the intermediate 2 (A = I) by transition metal catalyzed carbon-carbon bond-forming reactions. Antibacterial evaluation of compounds 2 with A = alkyl, ethenyl, ethynyl, hydroxyalkyl, aldo and keto, oximinoakyl, carboalkoxy, nitro, amino, halo and psi-halo, alkylthio, alkylsulfinyl, and alkysulfonyl against Staphylococcus aureus and Enterococcus faecalis led to the identification of several SAR trends. In several series of homologues (alkyl, ketyl, aximinoalkyl, amino, halo and psi-halo, and alkythio), antibacterial activity increased with increasing lipophilicity. But in series with where A is a substituent with a trior tetrasubstituted (substituent larger than H) quaternary atom attached directly to the aromatic ring (hydroxyalkyl, alkylsulfinyl, alkylsufonyl), the activity peaked at the member of the series with the "tert-butyl" connectivity pattern. Conjugated electron-withdrawing substituents also had increased activity relative to nonconjugated analogues of comparable lipophilicity.

Bis-aryl ureas have been disclosed previously as a potent class of Raf kinase inhibitors. Modifications in the amide portion led to an improvement in aqueous solubility, an important characteristic for an oral drug. Based on this finding, we hypothesize that this portion of the molecule is directed towards the solvent in Raf-1.

A simple pharmacophore point filter has been developed that discriminates between drug-like and nondrug-like chemical matter. It is based on the observation that nondrugs are often underfunctionalized. Therefore, a minimum count of well-defined pharmacophore points is required to pass the filter. The application of the filter results in 66-69% of subsets of the MDDR database to be classified as drug-like. Furthermore, 61-68% of subsets of the CMC database are classified as drug-like. In contrast, only 36% of the ACD are found to be drug-like. While these results are not quite as good as those obtained with recently described neural net approaches, the method used here has clear advantages. In contrast to a neural net approach and also in contrast to decision tree methods described recently, the pharmacophore filter has been developed by using "chemical wisdom" that is unbiased from fitting the structural content of specific drug databases to prediction models. Similar to decision tree methods, the pharmacophore point filter provides a detailed structural reason for the classification of each molecule as drug or nondrug. The pharmacophore point filter results are compared to neural net filter results. A statistically significant overlap between compounds recognized as drug-like validates both approaches. The pharmacophore point filter complements neural net approaches as well as property profiling approaches used as drug-likeness filters in compound library analysis and design.

Japanese medaka (Oryzias latipes) and channel catfish (Ictalurus punctatus) were investigated for carcinogenic response following a 28-day, 3 x/wk pulse exposure to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Five-wk-old medaka were exposed at concentrations of 0, 0.5, and 1.0 mg/L, and 5-mo-old catfish at concentrations of 0, 0.1, and 0.5 mg/L. In medaka, a total of 19 tumors including 2 branchioblastomas, 6 thyroid follicular adenomas and 1 adenocarcinoma, and 11 subcutaneous fibrosarcomas were observed in 16 of 96 MNNG-exposed fish. In catfish, a total of 37 tumors including 4 squamous cell carcinomas and 16 papillomas, 3 lipomas, 1 fibroma, 1 osteosarcoma, 4 branchioblastomas, 6 thymic epithelial tumors, and 2 generalized lymphosarcomas were observed in 34 of 172 MNNG-exposed fish. The induction of neoplasms in medaka was primarily in the gill, thyroid, and subcutis of the cervical and trunk regions, whereas in catfish skin, thymus, oro-pharynx, and hemopoietic tissues were also commonly affected. In both species, the neoplastic response was considered to be related to direct exposure of the tissues to MNNG. Some of these tumors have not been reported in the literature in either natural or experimental fish. The results also suggest species-specific differences in carcinogenic response following MNNG exposure.

A novel series of cognition enhancers was designed based on molecular modeling and X-ray structure analysis of EXP-9121 (2). This new series features a spirocyclic ring system that constrains the side chain substituents into the orientation seen in the X-ray crystal structure of 2. MM2 calculations preformed on 2 accurately predicted the solid state conformation. Compounds could be rapidly assembled using a bis-Michael addition reaction. Unfortunately, in vitro testing showed moderate activity at best, suggesting the X-ray structure of 2 does not mimic the bioactive conformation.

Introduction JI-101 is a highly selective and potent angiogenesis inhibitor with unique EphB4 activity that distinguishes it from other agents in clinical development. We report the preclinical pharmacology and early clinical experience with this compound. Procedures Lead optimization was used to identify cgi1842 (now JI-101) with a targeted activity profile that is selective and unique. JI-101 was tested in binding, enzymatic, and cell-based assays for activity against kinase and non-kinase targets. Preclinical in vivo testing for PK, PD, efficacy, and safety pharmacology was performed in mouse, rat, guinea pig, and dog. A Phase I clinical trial is underway: 12 patients have been treated thus far with 28-day oral daily dosing at 100 mg, 200 mg, 400 mg QD or at 200 mg BID. PK, PD, and imaging analyses have been performed. Data JI-101 has a MW of 466D and high ( Conclusions JI-101 potently inhibits 3 critical angiogenic kinases (VEGFR2, EphB4, and PDGFR) and is the only such “triple” angiogenesis inhibitor currently in development. JI-101 shows robust preclinical and clinical pharmacology and is well-tolerated to date in human trials. In tumors where EphB4 may play an oncogenic role, such as head and neck cancer, JI-101 may have anti-proliferative effects in addition to anti-angiogenic effects and should be amenable to combination therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 17.

Introduction: JI-101 is a highly selective and potent angiogenesis inhibitor with unique EphB4 activity that distinguishes it from other agents in clinical development. We report the preclinical pharmacology and early clinical experience with this compound. Procedures: Lead optimization was used to identify cgi1842 (now JI-101) with a targeted activity profile that is selective and unique. JI-101 was tested in binding, enzymatic, and cell-based assays for activity against kinase and non-kinase targets. Preclinical in vivo testing for PK, PD, efficacy, and safety pharmacology was performed in mouse, rat, guinea pig, and dog. A Phase I clinical trial is underway: 9 patients, 3/cohort, are being treated with 28-day oral daily dosing at 100 mg, 200 mg, and 400 mg. PK, PD, and imaging analyses are being performed. Data: JI-101 has a MW of 466D and high ( Conclusions: JI-101 potently inhibits 3 critical angiogenic kinases (VEGFR2, EphB4, and PDGFR) and is the only such “triple” angiogenesis inhibitor currently in development. JI-101 shows robust preclinical and clinical pharmacology and is well-tolerated to date in human trials. In tumors where EphB4 may play an oncogenic role, such as head and neck cancer, JI-101 may have anti-proliferative effects in addition to anti-angiogenic effects and should be amenable to combination therapy. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B11.

The 3-aryl-2-oxooxazolidinones are a new class of synthetic antibacterial agents that potently inhibit protein synthesis. An automated pulse labelling method with [3H]-lysine was developed with Bacillus subtilis to obtain additional quantitative activity data for structure-activity relationship studies with the oxazolidinones. Inhibition constants were calculated after a Logit fit of the data into the formula: % of control = 100/(1 + e[-B(X - A)]), where B is the slope of the model, X is the natural log of the inhibitor concentration and A is the natural log of the inhibitor concentration required to inhibit protein synthesis by 50% (ln IC50). When substituents at the 5-methyl position of the heterocyclic ring (B-substituent) were NHCOCH3, OH or Cl, the correlation coefficient was 0.87 between the MIC and IC50 values (for all compounds with MICs less than or equal to 16 micrograms/ml). The D-isomers of DuP 721 (A-substituent = CH3CO) and DuP 105 (A-substituent = CH3SO) gave MICs of 128 micrograms/ml and IC50s of greater than or equal to 50 micrograms/ml for protein synthesis, showing that only the L-isomers were active. By MIC testing, oxazolidinones with the B-substituent of NHCOCH3 and the A-substituent of CH3CO, NO2, CH3S, CH3SO2 or (CH3)2CH had comparable antibacterial potency; however, pulse labelling analysis showed that compounds with an A-substituent of CH3CO or NO2 were more potent inhibitors of protein synthesis.

Spectral characteristics of several simple substituted B,B-bis(mesityl)pyrroloboranes are reported which support a theoretical treatment by Bonacic-Koutecky and Michl (J. Am. Chem. Soc.107, 1765 (1985)) describing the excited states of simple aminoboranes as an example of twisted internal charge transfer. In the aminoboranes the pyrrolo moiety functions as the electron donor group and the empty p-orbital of the boron atom as the acceptor.

The synthesis and structure/activity studies of the effect of varying the "B" group in a series of oxazolidinone antibacterials (I) are described. Two synthetic routes were used: (1) alkylation of aniline with glycidol followed by dialkyl carbonate heterocyclization to afford I (A = H, B = OH), whose arene ring was further elaborated by using electrophilic aromatic substitution methodology; (2) cycloaddition of substituted aryl isocyanates with epoxides to give A and B with a variety of values. I with B = OH or Br were converted to other "B" functionalities by using SN2 methodology. Antibacterial evaluation of compounds I with A = acetyl, isopropyl, methylthio, methylsulfinyl, methylsulfonyl, and sulfonamido and a variety of different "B" groups against Staphylococcus aureus and Enterococcus faecalis concluded that the compounds with B = aminoacyl, and particularly acetamido, were the most active of those examined in each A series, possessing MICs in the range of 0.5-4 micrograms/mL for the most active compounds described.

Mise en evidence de la formation d'un ylure qui est dissocie en difluorocarbene et triphenylphosphine

Of 158 channel catfish (Ictalurus punctatus) exposed to N-methyl-N'-nitro-N-nitrosoguanidine [(MNNG) CAS:70-25-7] in water for 28 days, 2 developed disseminated lymphosarcoma. One fish was necropsied at 12 months and another at 18 months following exposure. Both fish had a massive neoplastic infiltration of the bilateral pairs of head and trunk kidneys from which the neoplastic cells appeared to originate. The neoplastic infiltration was also observed in the following: thymus, gills, oral mucosa, liver, skin, skeletal muscle of head-neck region, and to a lesser extent spleen and bone marrow. This is probably the first report of lymphosarcoma in channel catfish. Although the occurrence of lymphosarcoma in these 2 catfish appeared to be related to exposure to MNNG, the exact role MNNG played in the tumor formation was not determined.

Of 158 channel catfish (Ictalurus punctatus) exposed to N-methyl-N'-nitro-N-nitrosoguanidine [(MNNG) CAS:70-25-7] in water for 28 days, 2 developed disseminated lymphosarcoma. One fish was necropsied at 12 months and another at 18 months following exposure. Both fish had a massive neoplastic infiltration of the bilateral pairs of head and trunk kidneys from which the neoplastic cells appeared to originate. The neoplastic infiltration was also observed in the following: thymus, gills, oral mucosa, liver, skin, skeletal muscle of head-neck region, and to a lesser extent spleen and bone marrow. This is probably the first report of lymphosarcoma in channel catfish. Although the occurrence of lymphosarcoma in these 2 catfish appeared to be related to exposure to MNNG, the exact role MNNG played in the tumor formation was not determined.

Hexafluoroacetone trihydrate (HFA) was applied to the skin of pregnant rats from Day 6 through 16 of gestation. All rats were killed on Day 21 with uterine weights, fetal survival, number of resorptions, live fetal weights plus crown-rump lengths, and gross abnormalities by external examination determined at necropsy. The fetuses were processed for examination of visceral/neural anomalies and skeletal abnormalities. In a range-finding study, doses were from 2.3 to 90 mg/kg/day. At 90 mg/kg/day signs of maternal toxicity were observed. At 40 mg/kg/day and above, all but one of 36 fetuses were resorbed. At all doses nonlethal to fetuses, teratogenic effects were suggested. Based on maternal toxicity and embryolethality observed in the range-finding study, doses of either 1, 5, or 25 mg/kg/day were used in the main study. Fetal toxicity, measured by number of resorptions and live fetuses per litter, was evident at 25 mg/kg/day. At 5 and 25 mg/kg/day the mean fetal weights and crown-rump lengths were significantly lower than those of the controls and maternal weight gain was adversely affected. Teratogenic effects consisting of gross external, internal soft-tissue, and skeletal abnormalities were observed at 5 and 25 mg/kg/day. At 1 mg/kg/day a possible treatment-related increase in fetal gross external and internal soft-tissue abnormalities was observed.

Juvenile medaka were exposed to N-methyl-N'-nitro-N-nitrosoguanidine in water under static renewal conditions for 28 days. Two groups of 134 fish each were pulsed 3 times weekly at nominal concentrations of 1.0 and 0.5 mg/liter with N-methyl-N'-nitro-N-nitrosoguanidine dissolved in dimethylformamide. A third group of 134 fish was exposed to the solvent control, 0.01% dimethylformamide in water. Following the 28-day exposure, and during the recovery period, fish were sampled at intervals of approximately 0, 3, 6, and 9 months and examined grossly. Selected tissues were evaluated microscopically. Many tumor types developed in both N-methyl-N'-nitro-N-nitrosoguanidine exposure groups, but only the gill lesions will be discussed. Approximately 50% of the fish in both treatment groups died from gill damage in the second to third month of the recovery period. More than 90% of the surviving treated fish displayed gill lesions, which progressed from mild epithelial hyperplasia of gill filaments at 0-months recovery to epitheliomatous hyperplasia at 3 months and advanced to a more focal nodular appearance of gill filaments at 6 months. Eight to 9 months after the treatment period, at least four fish displayed branchial blastomas. The control fish had no gill lesions. Chemically induced gill tumors have not been previously observed in fish. Even gill tumors of unknown origin are very rare.

Aus den 0x0- Verbindungen (I) entstehen die Ethinyl-carbinole (II), die zu (III) acetyliert werden.