Boehringer Ingelheim (Canada)

Pyrrole derivatives are natural organic molecules that are important to the pharmaceutical industry due to their occurrence in nature and their use in a wide range of medical applications. In general, non-symmetric, 1,2,5-triaryl-substituted pyrroles are prepared either by Paal-Knorr condensation or cycloaddition that present synthetic challenges particularly if late-stage functionalization is required. The present study describes a modular approach to synthesizing 1,2,5-triarylpyrroles containing three different arene substituents. Using pyrrole ester building blocks, a sequence of decarboxylative cross-coupling and C-H arylation provides unsymmetrical 1,2,5-triarylpyrroles in a regioselective, stepwise manner; the scope and limitations of the sequence are disclosed.

ABSTRACT Background BI 764198 is a selective, oral transient receptor potential cation channel, subfamily C, member 6 inhibitor under investigation for focal segmental glomerulosclerosis. Research design and methods Phase I study in 44 Japanese male volunteers. Single dose part: BI 764198 20 mg (n = 6) vs. placebo (n = 2); multiple dose part: BI 764198 40, 80, or 160 mg (n = 9 each) or placebo (n = 9) as a single dose then multiple daily dosing for 2 weeks. Primary endpoint: participants with drug-related adverse events (DRAEs); secondary endpoints: pharmacokinetic. Results DRAEs were reported in 20.5% (9/44) of participants (total BI 764198 21.2% [7/33]; placebo 18.2% [2/11]), mostly diarrhea (total BI 764198 15.2% [5/33]; placebo 18.2% [2/11]) and headache (BI 764198 80 mg 11.1% [1/9]; BI 764198 160 mg 33.3% [3/9]). BI 764198 exposure increased near dose proportionally to 80 mg and was slightly higher than anticipated with 160 mg. Pharmacokinetics were similar in Asians and non-Asians after accounting for body weight. Limitations include small sample size per dose and short trial duration. Conclusions BI 764198 was well tolerated; exposure increased near dose proportionally to 80 mg, as previously observed in predominantly White volunteers. Clinical trial registration This study was registered on Clinical Trials.gov, identifier NCT04665700.

The rising prevalence of liver diseases related to obesity and excessive use of alcohol is fuelling an increasing demand for accurate biomarkers aimed at community screening, diagnosis of steatohepatitis and significant fibrosis, monitoring, prognostication and prediction of treatment efficacy. Breakthroughs in omics methodologies and the power of bioinformatics have created an excellent opportunity to apply technological advances to clinical needs, for instance in the development of precision biomarkers for personalised medicine. Via omics technologies, biological processes from the genes to circulating protein, as well as the microbiome - including bacteria, viruses and fungi, can be investigated on an axis. However, there are important barriers to omics-based biomarker discovery and validation, including the use of semi-quantitative measurements from untargeted platforms, which may exhibit high analytical, inter- and intra-individual variance. Standardising methods and the need to validate them across diverse populations presents a challenge, partly due to disease complexity and the dynamic nature of biomarker expression at different disease stages. Lack of validity causes lost opportunities when studies fail to provide the knowledge needed for regulatory approvals, all of which contributes to a delayed translation of these discoveries into clinical practice. While no omics-based biomarkers have matured to clinical implementation, the extent of data generated has enabled the hypothesis-free discovery of a plethora of candidate biomarkers that warrant further validation. To explore the many opportunities of omics technologies, hepatologists need detailed knowledge of commonalities and differences between the various omics layers, and both the barriers to and advantages of these approaches.

Das Darmmikrobiom ist bei jedem Menschen einzigartig. Es hat einen großen Einfluss auf die Gesundheit. Oral verabreichte Probiotika werden zur Vorbeugung und/oder Behandlung von Magen-Darm-Erkrankungen eingesetzt. Darüber hinaus zeigen sie Potenzial bei der Behandlung anderer Erkrankungen, die nicht auf Magen-Darm-Störungen zurückzuführen sind. In-vitro-Studien ermöglichen ein besseres Verständnis der biologischen Eigenschaften therapeutisch verwendeter Mikroorganismen und der positiven Wirkungen, die sie in vivo haben können.

BackgroundInterstitial lung disease (ILD) is one of the major causes of morbidity and mortality in patients with idiopathic inflammatory myopathies (IIM). [1] Within IIM, ILD is frequently found in patients with anti-synthetase syndrome (ASyS). Current treatment is based on a combination of high doses of glucocorticoids and other immunosuppressors such as cyclophosphamide, with progression of ILD despite the treatment. One anti-fibrotic drug, nintedanib, has recently been approved for patients with progressive fibrotic ILD.ObjectivesTo explore if within patients with ASyS there is a group with worsening ILD that fits the definition of progressive pulmonary fibrosis (PPF)[2] and thus would be eligible for anti-fibrotic treatment.[3]MethodsA single center based retrospective cohort of patients diagnosed with ASyS, ILD involvement, and positivity for specific autoantibodies anti-Jo1, anti-PL7, anti-PL12, anti-EJ and/or anti-OJ (ASyS-AB) was identified using the Swedish Myositis network register. We selected the latest computed tomography (CT) thoracic scans, pulmonary function tests (PFT) and the development of respiratory symptoms according to clinical records. Patients were evaluated based on the INBUILD study criteria[3] and the international thoracic and respiratory clinical practice guideline (CPG)[2] for the presence of PPF. An experienced thoracic radiologist reviewed the CT scans of those who met the criteria to confirm PPF.ResultsWe identified 147 individuals positive for ASyS-AB; 66 of them were not included due to either a follow-up period of less than one year, lack of data in the national registry or absence of ILD. Finally, a cohort of 81 patients was included, 67.9% women, with a median (Q1,Q3) age at disease onset of 58 (48,67) years (Table 1). The median time from disease onset until assessment for PPF criteria was of 6 years.The most prevalent CT finding amongst all groups was fibrotic changes (n=28) neither fitting the usual interstitial pneumonia (UIP) (n=9) nor the fibrotic non-specific interstitial pneumonia (NSIP) (n=6) criteria; followed by inflammatory NSIP (n= 18). 14.8 percent or 19.8 percent (INBUILD and CPG, retrospectively) of the individuals with any type of lung fibrotic pattern on CT met the definition of PPF.Table 1.Baseline characteristics of patients with anti-synthetase syndrome (ASyS) in the cohortTotalBy antibodyPL7,n=8PL12,n=8Jo1,n=58EJ,n=4OJ,n=3Women, n (%)55 (67.9)6 (75)5 (62.5)40 (69)3 (75)1 (33.3)Median age at disease onset, years (Q1,Q3)58 (48,67)61 (35,68)61 (48,67)56 (47,65)72 (46,76)61 (55,74)Time since disease onset at evaluation, years (Q1,Q3)6 (3,11)10 (3,22)4 (2,5)7 (3,13)2 (2,15)4 (1,7)Patients meeting criteria for progressive fibrosis, n (%)INBUILD criteria12 (14.8)2 (25)1 (12.5)8 (13.8)0 (0)1 (33.3)ATS/ERS/JRS Clinical practice guidelines14 (17.3)3 (37.5)1 (12.5)10 (17.2)0 (0)0 (0)Time since disease onset at evaluation, years (Q1,Q3)10 (5,21)-----ConclusionIn this cross-sectional study, 15% of patients with ASyS fulfilled the definition of progressive fibrosis and thus could be eligible for anti-fibrotic treatment. To our knowledge, this is the first cohort to demonstrate a possible real-life target of anti-fibrotics in IIM-ILD.