Author: de Jong, Pim A. ; Gallardo-Estrella, Leticia ; Humphries, Stephen M. ; Kwee, Anastasia K A L ; Lynch, David A ; Tiddens, Harm A W M ; Kwee, Anastasia K.A.L. ; de Jong, Pim A ; van der Veer, Tjeerd ; Andrinopoulou, Eleni-Rosalina ; Tiddens, Harm A.W.M. ; Charbonnier, Jean-Paul ; Lynch, David A. ; Pompe, Esther ; Humphries, Stephen M

BACKGROUNDIn chronic obstructive pulmonary disease (COPD), vascular alterations have been shown to contribute to hypoxia and pulmonary hypertension, but the independent contribution of small vessel abnormalities to mortality remains unclear.METHODSWe quantified artery and vein dimensions on computed tomography (CT) down to 0.2 mm. Small vessel volumes (<1 mmᴓ) were normalized by body surface area. In 7903 current and former smokers of the COPDGene study (53.2% male) the independent contribution of small artery and small vein volume to all-cause mortality was tested in multivariable Cox models. Additionally, we calculated the 95^th percentile of small arteries and veins in 374 never smokers to create two groups: normal and high small artery or vein volume. We describe clinical, physiological and imaging characteristics of subjects with a high small artery and high small vein volume.FINDINGSBoth high small artery and high small vein volumes were independently associated with mortality with an adjusted hazard ratio of 1.07 [1.01, 1.14] and 1.34 [1.21, 1.49] per mL/m² increase, respectively. In COPDGene, 447 (5.7%) had high small artery volume and 519 (9.1%) subjects had high small vein volume and both had more emphysema, more air trapping and more severe coronary calcium.INTERPRETATIONIn smokers, abnormally high volumes in small arteries and veins are both relevant for mortality, which urges investigations into the aetiology of small pulmonary vessels and cardiac function in smokers.FUNDINGAward Number U01-HL089897 and U01-HL089856 from the NHLBI. COPD Foundation with contributions from AstraZeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion.

28 Mar 2024·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery and Optimization of Selective Brain-Penetrant EBP Inhibitors that Enhance Oligodendrocyte Formation

Q1 · MEDICINE

Article

Author: McHugh, Daniel ; Salphati, Laurent ; Volgraf, Matthew ; Pang, Jodie ; Ung, Peter M.-U. ; Factor, Daniel C. ; Sun, Dawei ; Meklemburg, Robert ; Korman, Allison J. ; Tesar, Paul J. ; Dere, Edward ; Carruthers, Nicholas ; Payandeh, Jian ; Li, Tianbo ; Castanedo, Georgette M. ; Janota, Danielle ; Masureel, Matthieu ; Braun, Marie-Gabrielle ; Harper, Halie E. ; Adams, Drew J. ; Dorel, Ruth ; Baumann, Hannah ; Stubblefield, Samantha ; Lang, Bradley T.

The inhibition of emopamil binding protein (EBP), a sterol isomerase within the cholesterol biosynthesis pathway, promotes oligodendrocyte formation, which has been proposed as a potential therapeutic approach for treating multiple sclerosis. Herein, we describe the discovery and optimization of brain-penetrant, orally bioavailable inhibitors of EBP. A structure-based drug design approach from literature compound 1 led to the discovery of a hydantoin-based scaffold, which provided balanced physicochemical properties and potency and an improved in vitro safety profile. The long half-lives of early hydantoin-based EBP inhibitors in rodents prompted an unconventional optimization strategy, focused on increasing metabolic turnover while maintaining potency and a brain-penetrant profile. The resulting EBP inhibitor 11 demonstrated strong in vivo target engagement in the brain, as illustrated by the accumulation of EBP substrate zymostenol after repeated dosing. Furthermore, compound 11 enhanced the formation of oligodendrocytes in human cortical organoids, providing additional support for our therapeutic hypothesis.

01 Nov 2023·BMJ Open Diabetes Research & Care

Prescribing of evidence-based diabetes pharmacotherapy in patients with metabolic dysfunction-associated steatohepatitis

Article

Author: Parish, Alice ; Moylan, Cynthia ; Olsen, Maren ; Crowley, Matthew J ; Alexopoulos, Anastasia-Stefania ; Batch, Bryan C

IntroductionMetabolic dysfunction-associated steatohepatitis (MASH) is highly prevalent in type 2 diabetes (T2D). Pioglitazone and glucagon-like peptide-1 receptor agonists (GLP-1RA) are medications used in T2D that can resolve MASH and should be considered in all patients with T2D and MASH. We assessed prescription rates of evidence-based T2D pharmacotherapy (EBP) in MASH, and ascertained racial/ethnic disparities in prescribing.Research design and methodsWe conducted a cross-sectional study on patients in Duke University Health System with diagnosis codes for T2D and MASH between January 2019 and January 2021. Only patients with ≥1 primary care or endocrinology encounter were included. The primary outcome was EBP, defined as ≥1 prescription for pioglitazone and/or a GLP-1RA during the study period. A multivariable logistic regression model was used to examine the primary outcome.ResultsA total of 847 patients with T2D and MASH were identified; mean age was 59.7 (SD 12) years, 61.9% (n=524) were female, and 11.9% (n=101) and 4.6% (n=39) were of Black race and Latino/a/x ethnicity, respectively. EBP was prescribed in 34.8% (n=295). No significant differences were noted in the rates of EBP use across racial/ethnic groups (Latino/a/x vs White patients: adjusted OR (aOR) 1.82, 95% CI 0.78 to 4.28; Black vs White patients: aOR 0.76, 95% CI 0.44 to 1.33, p=0.20).ConclusionsEBP prescriptions, especially pioglitazone, are low in patients with T2D and MASH, regardless of race/ethnicity. These data underscore the need for interventions to close the gap between current and evidence-based care.

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Indication	Highest Phase	Country/Location	Organization	Date
Multiple Sclerosis	Discovery	US	Genentech, Inc.	12 Mar 2024

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