The monoalkyl derivatives of urea have long been known to possess hypnotic properties. While the relative effects of alkyl groups on hypnotic activity have been studied,1 few attempts have been made to study the effects produced by the presence of substituted alkyl groups.With this fact in mind it was decided to prepare and study some hydroxyalkyl-substituted ureas.It was to be expected that the presence of the hydroxyl group would produce a decrease in hypnotic activity as well as lower the toxicity. One of the necessary qualifications a hypnotic must have is a safe margin between the effective dose and the toxic dose, and since the presence of the hydroxyl group affects both, it was hoped that such a combination might be obtained in this way.The starting materials for these compounds were the alkanolamines except in one case where 6-aminothymol was used. These amino compounds when treated with nitrourea yielded the corresponding hydroxyalkyl ureas.In addition to the simple substituted ureas certain of their derivatives appeared to be of interest. The p-aminobenzoyl and cinnamoyl derivatives were prepared. Since many of the esters of p-aminobenzoic acid and cinnamic acid have local anesthetic properties, it was thought that the corresponding carbamidoalkyl esters of these two acids might have similar properties.Two of the hydroxyalkylureas, /3-hydroxyethylurea2 and unsym.-ái-ß-hydroxyethylurea3 had been previously prepared. The remaining hydroxyalkylureas as well as the derivatives of all of the hydroxyalkylureas represent new compounds.
Background: The treatment landscape of nonalcoholic steatohepatitis (NASH) is changing rapidly; drug safety is key as most patients will need long-term treatment. Cenicriviroc (CVC) is an oral antagonist of C-C chemokine receptors 2/5 in Phase 3 development for NASH. We report cumulative safety data from CVC studies. Methods: Studies included single- and multi-dose Phase 1 in healthy volunteers and cirrhosis, Phase 2 in NASH and HIV-1, and Phase 3 in progress. Treatment-emergent AEs (TEAEs), lab abnormalities, and causality were assessed. Results: As of July 2018, >1220 adults received CVC and had available safety data. In Phase 1 studies (N=580), TEAEs in ≥2% of CVC subjects included headache, nasopharyngitis, abdominal pain, nausea, vomiting, diarrhea, contact dermatitis, and somnolence in single-dose studies, and headache and constipation in multi-dose studies, mostly mild or moderate. In Child-Pugh A or B cirrhosis subjects (n=16), CVC dosing for 14 days was well tolerated, with no safety concerns identified. Single-dose administration was well tolerated in subjects with severe hepatic impairment (Child-Pugh C). In Phase 2 studies (N=442), incidence and severity of TEAEs, discontinuation due to TEAEs, and lab abnormalities were similar in CVC vs. comparator; no life-threatening TEAEs (Grade 4) or deaths occurred with CVC. In subjects with NASH and liver fibrosis on CVC for 1 year (n=144), TEAEs in ≥2% of subjects of at least moderate severity (Grade ≥2) were fatigue (2.8%) and diarrhea (2.1%). One serious AE (SAE) [0.3%] was assessed as drug related (Grade 2 arrhythmia). CVC was well tolerated in a 10-day dose-escalation study in HIV-1 (n=44). In HIV patients treated with ≤48 weeks of CVC (n=115), Grade ≥2 TEAEs in ≥2% of subjects were nausea (2.0%). No SAE was assessed as drug related. One CVC subject discontinued due to an AE (Grade 2 depression). To date in Phase 3, no new safety signals have been identified. Conclusions: CVC was safe in >1200 subjects treated to date, including those with NASH and liver fibrosis, HIV-1, and hepatic impairment. Disclosure M.F. Abdelmalek: Advisory Panel; Self; Allergan, Bristol-Myers Squibb Company, Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Prometic Life Sciences Inc. Consultant; Self; TaiwanJ Pharmaceuticals Co., Ltd. Research Support; Self; Akcea Therapeutics, Allergan, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Conatus Pharmaceuticals Inc., Galectin Therapeutics Inc., GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Novartis Pharmaceuticals Corporation, Prometheus, Shire, TaiwanJ Pharmaceuticals Co., Ltd. Speaker's Bureau; Self; Alexion Pharmaceuticals, Inc. R.W. Charlton: Employee; Self; Allergan. E.B. Martins: Employee; Self; Allergan. Stock/Shareholder; Self; Allergan. B. Tan: Employee; Self; Allergan. A.D. Coviello: Consultant; Self; Novo Nordisk Inc. Research Support; Self; Allergan, Bristol-Myers Squibb Company, GENFIT. Speaker's Bureau; Self; Novo Nordisk Inc. N. Alkhouri: Speaker's Bureau; Self; Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc. Other Relationship; Self; Allergan, GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Madrigal.
Background: Hepatic fat accumulation modulates innate immunity causing recruitment of bone marrow derived macrophages/activation of Kupffer cells, resulting in inflammatory changes associated with the development of insulin resistance and NASH. Monocyte recruitment/infiltration into the liver is mediated by C-C chemokine receptor 2 (CCR2). CCR5 promotes obesity-induced insulin resistance/hepatic steatosis in murine models. Cenicriviroc (CVC) is an oral CCR2/CCR5 antagonist in Phase 3 development for NASH. We evaluated effects of CVC on inflammatory cytokines and HbA1c in NASH subjects. Methods: Adults with NASH and liver fibrosis were randomized 1:1 to CVC 150 mg or placebo (PBO) [Phase 2 CENTAUR study]. Cytokines and metabolic parameters were assessed. Results: In 289 randomized adults (mean age 54 years, mean BMI 33.9 kg/m2, 52.0% diabetes), CCL2 significantly increased from baseline (BL) in CVC vs. PBO. For CVC, hs-CRP, IL-6, IL-8 and IL-1β decreased from BL; HbA1c decreased for CVC at all time points but increased for PBO at Days 180 and 360 (Table). Changes were consistent over time and more pronounced in those with advanced liver fibrosis. Conclusions: CVC was associated with elevation of CCL2 and decreased hs-CRP/inflammatory cytokines, suggesting strong target engagement and a therapeutic impact on the inflammatory milieu associated with insulin resistance that may be reflected in lower HbA1c. Disclosure A.D. Coviello: Consultant; Self; Novo Nordisk Inc. Research Support; Self; Allergan, Bristol-Myers Squibb Company, GENFIT. Speaker's Bureau; Self; Novo Nordisk Inc. R.W. Charlton: Employee; Self; Allergan. E.B. Martins: Employee; Self; Allergan. Stock/Shareholder; Self; Allergan. J. Yuan: None. N. Alkhouri: Speaker's Bureau; Self; Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc. Other Relationship; Self; Allergan, GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Madrigal. M.F. Abdelmalek: Advisory Panel; Self; Allergan, Bristol-Myers Squibb Company, Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Prometic Life Sciences Inc. Consultant; Self; TaiwanJ Pharmaceuticals Co., Ltd. Research Support; Self; Akcea Therapeutics, Allergan, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Conatus Pharmaceuticals Inc., Galectin Therapeutics Inc., GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Novartis Pharmaceuticals Corporation, Prometheus, Shire, TaiwanJ Pharmaceuticals Co., Ltd. Speaker's Bureau; Self; Alexion Pharmaceuticals, Inc.
Background: Nonalcoholic steatohepatitis (NASH) is considered the hepatic manifestation of type 2 diabetes and can progress to advanced fibrosis (AF), associated with significant increase in morbidity and mortality. CVC is an oral C-C chemokine receptor 2/5 antagonist being evaluated to treat liver fibrosis in adults with NASH. This study describes antifibrotic effects seen in the Phase 2b CENTAUR study overall and those with AF (F3) specifically. Methods: Adults with confirmed NASH, nonalcoholic fatty liver disease activity score ≥4, and liver fibrosis Stages F1-3 (NASH CRN) received CVC 150 mg daily (Arm A) or placebo (PBO; Arm C) for 2 years; Arm B received PBO in Year (Y)1 and CVC in Y2. Liver biopsies were assessed blind at baseline (BL), Y1, and Y2 by a central pathologist. Improvement in fibrosis and serum inflammatory markers were assessed in subjects with evaluable biopsies at BL, Y1, and Y2 (modified intent-to-treat [mITT] population). Results: Of 289 adults randomized (mean age 54 years, mean BMI 33.9 kg/m2, 52.0% diabetes), 28.6% (36/126) vs. 19.0% (24/126) achieved ≥1-stage fibrosis improvement at Y1 in CVC vs. PBO arms (mITT) overall. Of 97 AF subjects at BL (mean age 57.8 years, mean BMI 34.1 kg/m2, 69.0% diabetes), 38.3% (18/47) vs. 28.0% (14/50) achieved this endpoint in CVC vs. PBO arms (mITT). Overall, 60.0% (18/30) in Arm A vs. 30.0% (3/10) in Arm C maintained benefit at Y2 (mITT). In AF subjects, 85.7% (12/14) in Arm A vs. 60.0% (3/5) in Arm C maintained benefit at Y2 (mITT). Greater reductions in hs-CRP, fibrinogen, IL-6, IL-8, and IL-1β were observed with CVC. In AF subjects, these changes were more pronounced. Overall and with AF, adverse events were comparable for CVC and PBO; no deaths occurred. Conclusion: CVC was well tolerated and provided antifibrotic benefit in adults with NASH and fibrosis, especially those with AF. Most subjects achieving ≥1-stage fibrosis improvement at Y1 maintained benefit at Y2, with reductions in inflammatory biomarkers, supporting the ongoing Phase 3 study of CVC in NASH. Disclosure N. Alkhouri: Speaker's Bureau; Self; Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc. Other Relationship; Self; Allergan, GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Madrigal. R.W. Charlton: Employee; Self; Allergan. E.B. Martins: Employee; Self; Allergan. Stock/Shareholder; Self; Allergan. H. Landgren: Employee; Self; Allergan. A.D. Coviello: Consultant; Self; Novo Nordisk Inc. Research Support; Self; Allergan, Bristol-Myers Squibb Company, GENFIT. Speaker's Bureau; Self; Novo Nordisk Inc. M.F. Abdelmalek: Advisory Panel; Self; Allergan, Bristol-Myers Squibb Company, Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Prometic Life Sciences Inc. Consultant; Self; TaiwanJ Pharmaceuticals Co., Ltd. Research Support; Self; Akcea Therapeutics, Allergan, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Conatus Pharmaceuticals Inc., Galectin Therapeutics Inc., GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Novartis Pharmaceuticals Corporation, Prometheus, Shire, TaiwanJ Pharmaceuticals Co., Ltd. Speaker's Bureau; Self; Alexion Pharmaceuticals, Inc.
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