Drug-induced lung fibrosis is a debilitating disease, linked to high morbidity and mortality. A number of drugs can cause fibrosis, many of which are used to treat cancer, including chemotherapy agents and immune checkpoint inhibitors. The MRTF/SRF transcription pathway has been proposed as a potential therapeutic target, as it is critical for myofibroblast differentiation, a hallmark of fibrosis. In human lung fibroblasts, the MRTF/SRF pathway inhibitor, CCG-257081, effectively decreased mRNA levels of downstream genes: smooth muscle actin and connective tissue growth factor, with IC 50 s of 4 and 15 μM, respectively. The ability of CCG-257081 to prevent inflammation and fibrosis, measured via pulmonary collagen content and histopathology, was tested in a murine model of chemotherapy-induced lung fibrosis. Animals were given intraperitoneal bleomycin for four weeks, and concurrently dosed with CCG-257081 (0, 10, 30, and 100 mg/kg PO), a clinical anti-fibrotic (nintedanib), or clinical standard of care (prednisolone). Mice treated with 100 mg/kg CCG-257081 gained weight vs. vehicle-treated control mice, while those receiving nintedanib and prednisolone lost significant weight. Hydroxyproline content and histological findings in tissue of animals on 100 mg/kg CCG-257081 were not significantly different from naive tissue, indicating successful prevention. Measures of tissue fibrosis were comparable between CCG-257081 and nintedanib, but only the MRTF/SRF inhibitor decreased plasminogen activator inhibitor-1 (PAI-1), a marker linked to fibrosis, in bronchoalveolar lavage fluid. Prednisolone led to marked increases in lung fibrosis. This study demonstrates the potential use of MRTF/SRF inhibitors to prevent drug-induced lung fibrosis in a clinically relevant model of drug-induced disease.

RATIONALE:Low high-density lipoprotein-cholesterol (HDL-C) in patients with coronary heart disease (CHD) may be caused by rate-limiting amounts of lecithin:cholesterol acyltransferase (LCAT). Raising LCAT may be beneficial for CHD, as well as for familial LCAT deficiency, a rare disorder of low HDL-C.OBJECTIVE:To determine safety and tolerability of recombinant human LCAT infusion in subjects with stable CHD and low HDL-C and its effect on plasma lipoproteins.METHODS AND RESULTS:A phase 1b, open-label, single-dose escalation study was conducted to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of recombinant human LCAT (ACP-501). Four cohorts with stable CHD and low HDL-C were dosed (0.9, 3.0, 9.0, and 13.5 mg/kg, single 1-hour infusions) and followed up for 28 days. ACP-501 was well tolerated, and there were no serious adverse events. Plasma LCAT concentrations were dose-proportional, increased rapidly, and declined with an apparent terminal half-life of 42 hours. The 0.9-mg/kg dose did not significantly change HDL-C; however, 6 hours after doses of 3.0, 9.0, and 13.5 mg/kg, HDL-C was elevated by 6%, 36%, and 42%, respectively, and remained above baseline ≤4 days. Plasma cholesteryl esters followed a similar time course as HDL-C. ACP-501 infusion rapidly decreased small- and intermediate-sized HDL, whereas large HDL increased. Pre-β-HDL also rapidly decreased and was undetectable ≤12 hours post ACP-501 infusion.CONCLUSIONS:ACP-501 has an acceptable safety profile after a single intravenous infusion. Lipid and lipoprotein changes indicate that recombinant human LCAT favorably alters HDL metabolism and support recombinant human LCAT use in future clinical trials in CHD and familial LCAT deficiency patients.CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01554800.

Background: Gemcabene (Gem) is a late-stage Phase 2 clinical candidate being evaluated for the reduction of low-density lipoprotein cholesterol (LDL-C) in homozygous familial hypercholesterolemia (HoFH) patients. Combination therapy includes statins as standard of care to treat this genetic disorder. LDL-deficient (LDLr) mice have been widely used with lipid-lowering agents to demonstrate LDL-C lowering with good translation to clinical efficacy. We have previously shown that atorvastatin (Atorva) reduces LDL-C and apoB in the LDLr deficient mice and in casein-fed (endogenous hypercholesterolemic) rabbits. Experiment and Results: In the current study, we assessed Gem and Atorva effects alone and in combination on reduction of LDL-C in chow-fed LDLr deficient mice, an animal model of HoFH. Baseline LDL-C and total cholesterol were 246±20 mg/dL and 329±23 mg/dL in these mice Female LDLr deficient mice (n=10) were treated with Atorva alone (60mg/kg/day), Gem alone (60/mg/kg/day) or the agents combined (Atorva + Gem)(each at 60 mg/kg/day) for 14 days. Following treatments with Atorva, Gem, and Atorva+Gem, fasting LDL-C reduced by 22%, 55% and 72%, respectively, and total cholesterol by 21%, 47%, and 58%, respectively; showing additional reduction of 50% LDL-C by Gem on top of Atorva alone. Since LDLr are absent in these mice, similar to HoFH patients, the LDL-C lowering by Gem could be due to reduced VLDL production rates. Indeed, our studies in rat hepatocytes and in apoB100-only mice (apobec-1 knockout) showed reduced radioactivity in cholesterol and triglyceride fractions in the hepatocytes and in the plasma and liver of mice administered 14C acetate, suggesting cholesterol and fatty acid synthesis inhibition as a mechanism of LDL-C lowering. Gem also enhances the clearance of VLDL in normal rats. We propose both mechanisms may contribute to LDL-C reduction in LDLr deficient mice. A more detailed kinetic study of Gem in LDLr deficient models is underway to verify these proposed mechanisms. Conclusions: Gemcabene alone and combined with atorvastatin significantly (55-72%) reduced LDL-C in this predictive in-vivo HoFH disease model. These findings suggest that treatment with Gem on top of standard of care therapy by statins may benefit HoFH patients.

Introduction: Lecithin cholesterol acyltransferase (LCAT) is a liver-derived enzyme in plasma that catalyzes the formation of cholesteryl esters (CE). Mutations in the human LCAT gene result in familial LCAT deficiency (FLD), characterized by absent high-density lipoprotein cholesterol (HDL-C), corneal opacities, anemia, and severe renal disease. Replacing the defective enzyme should restore the normal level of plasma CE (LCAT product) and lead to the appearance of alpha HDL (α-HDL) lipoproteins. Aim: To assess the formation of CE and the appearance of HDL over time in a FLD patient with recombinant human LCAT (ACP-501). Methods: A FLD subject with very low HDL-C (<5 mg/dL), corneal opacities, stage 4/5 renal disease, anemia, and splenomegaly received a 1 hour infusion of recombinant human LCAT (rhLCAT) and serial plasma samples were collected over 7 days. Results: HDL-C increased from <5 mg/dL to 17 mg/dL at 8 hours and remained measurable for 7 days. CE increased rapidly, doubling in concentration within 2 hours, and sustained a higher concentration than HDL over 7 days. An increase in LDL-C was delayed about 6 hours suggesting CETP transfer of CE from HDL to LDL. Small sized particles were rapidly converted to HDL2 and HDL3 sized particles on FPLC. Large α-HDL appeared on agarose electrophoresis within 30 minutes. ApoAI Western blot analysis confirmed the rapid generation of apoAI staining α-HDL. α-1, 2 and 3 particles rapidly appeared by 2-D gel electrophoresis. Filipin stained 1-D gels revealed large α particles that persisted for 7 days. α-4 sized particles decreased as α-HDL formed. Sudan stained 1-D gels showed the generation of CE-rich α-HDL. Conclusions: The infusion of rhLCAT (ACP-501) in a lecithin cholesterol acyltransferase deficient subject with no HDL rapidly generated CE and α-HDL with evidence of sustained activity over 7 days. CE appeared in LDL suggesting the transfer of CE from HDL to LDL by CETP. The lipid and lipoprotein changes are consistent with normal HDL maturation.

Previously, scanning mutagenesis studies of the insecticidal peptide omega-hexatoxin-Hv1a identified a set of structural features used by the omega-hexatoxin-1 family to modulate insect calcium channels. These structural features were re-purposed as a 3D search term (i.e., a pharmacophore model) for mining commercially available compound databases, and screening of 1370 of the resultant candidate compounds against larvae of the mosquito Aedes aegypti and the beet armyworm Spodoptera exigua yielded insecticidal leads. One family of lead compounds, typified by a triazine core, showed inhibitory activity against voltage-gated calcium currents of cockroach DUM neurons and was optimized with guidance from SAR studies and the 3D search term. This led to characterization of a class of aryl triazines with greatly increased activity against both mosquitoes and lepidopterans. To our knowledge, discovery of such an active class of lead compounds using such a small set of pre-screened candidate compounds—selected on the basis of a pharmacophore model derived from an insecticidal venom peptide—is not precedented in the literature.

The design of drugs with selective tissue distribution can be an effective strategy for enhancing efficacy and safety, but understanding the translation of preclinical tissue distribution data to the clinic remains an important challenge. As part of a discovery program to identify next generation liver selective HMG-CoA reductase inhibitors we report the identification of (3R,5R)-7-(4-((3-fluorobenzyl)carbamoyl)-5-cyclopropyl-2-(4-fluorophenyl)-1H-imidazol-1-yl)-3,5-dihydroxyheptanoic acid (26) as a candidate for treating hypercholesterlemia. Clinical evaluation of 26 (PF-03491165), as well as the previously reported 2 (PF-03052334), provided an opportunity for a case study comparison of the preclinical and clinical pharmacokinetics as well as pharmacodynamics of tissue targeted HMG-CoA reductase inhibitors.

AbstractIntroduction:As Hurricane Katrina bore down on New Orleans in August 2005, the city's mandatory evacuation prompted the exodus of an estimated 80% of its 485,000 residents. According to estimates from the US Centers for Disease Control and Prevention (CDC), at least 18 states subsequently hosted >200,000 evacuees.Hypothesis/Problem:In this case study, “Operation Helping Hands” (OHH), the Massachusetts health and medical response in assisting Hurricane Katrina evacuees is described. Operation Helping Hands represents the largest medical response to evacuees in recent Massachusetts history.Methods:The data describing OHH were derived from a series of structured interviews conducted with two leading public health officials directing planning efforts, and a sample of first responders with oversight ofoperations at the evacuation site. Also, a literature review was conducted to identify similar experiences, common challenges, and lessons learned.Results:Activities and services were provided in the following areas: (1) administration and management;(2) medical and mental health; (3) public health; and (4) social support. This study adds to the knowledge base for future evacuation and shelter planning, and presents a conceptual framework that could be used by other researchers and practitioners to describe the process and out comes of similar operations.Conclusions:This study provides a description of the planning and implementation efforts of the largest medical evacuee experience in recent Massachusetts history, an effort that involved multiple agencies and partners. The conceptual framework can inform future evacuation and shelter initiatives at the state and national levels, and promotes the overarching public health goal of the highest attainable standard of health for all.

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Cannabinoid-1 (CB(1)) receptor antagonists exhibit pharmacological properties favorable to treatment of obesity, caused by both centrally mediated effects on appetite and peripherally mediated effects on energy metabolism. However, the relative contribution of these effects to the weight loss produced by CB(1) receptor antagonists remains unclear. Here, we compare food intake-related and independent effects of the CB(1) selective antagonist 1-(7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5] triazin-4-yl)-3-(methylamino) azetidine-3-carboxamide (PF-95453) in obese cynomolgus monkeys. Monkeys were divided into three study groups (n = 10 each) and treated once daily for 8 weeks with either vehicle or PF-95453 as follows: 1, fed ad libitum and dosed orally with vehicle; 2, fed ad libitum and dosed orally with PF-95453 (0.5 mg/kg weeks 1-3, 1.0 mg/kg weeks 4-8); and 3, fed an amount equal to the amount consumed by the drug-treated group and dosed orally with vehicle (pair-fed). PF-95453 treatment significantly reduced food consumption by 23%, body weight by 10%, body fat by 39%, and leptin by 34% while increasing adiponectin by 78% relative to vehicle-treated controls. Pairfed animals did not exhibit reductions in body weight or leptin but did show significantly reduced body fat (11%) and increased adiponectin (15%) relative to vehicle-treated controls but markedly less than after PF-95453 treatment. Indeed, significant differences were noted between the drug-treated and pair-fed groups with respect to body weight reduction, body fat reduction, increased adiponectin, and leptin reduction. Similar to humans, monkeys treated with the CB(1) receptor antagonist exhibited decreased body weight and body fat, a substantial portion of which seemed to be independent of the effects on food intake.

Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of lipid and glucose metabolism. PPAR gamma agonists improve insulin sensitivity and hyperglycemia and are effective in treating type 2 diabetes mellitus (T2DM), whereas PPAR alpha agonists are used to treat dyslipidemia and atherosclerosis. The goal here was to examine the efficacy of a selective PPAR alpha agonist {(S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP-900691} on lipid, glycemic, and inflammation indices in 14 cynomolgus monkeys with spontaneous T2DM maintained on daily insulin therapy. Monkeys were dosed orally with either vehicle (n = 7) or CP-900691 (3 mg/kg, n = 7) daily for 6 weeks. CP-900691 treatment increased plasma high-density lipoprotein cholesterol (HDLC) (33 +/- 3 to 60 +/- 4 mg/dL, p < 0.001) and apolipoprotein A1 (96 +/- 5 to 157 +/- 5 mg/dL, p < 0.001), reduced plasma triglycerides (547 +/- 102 to 356 +/- 90 mg/dL, p < 0.01), and apolipoprotein B (62 +/- 3 to 45 +/- 3 mg/dL, p < 0.01), improved the lipoprotein index (HDL to non-HDLC ratio; 0.28 +/- 0.06 to 0.79 +/- 0.16, p < 0.001), decreased body weight (p < 0.01) and C-reactive protein (CRP) (1700 +/- 382 to 304 +/- 102 ng/ml, p < 0.01), and increased adiponectin (1697 +/- 542 to 4242 +/- 1070 ng/ml, p < 0.001) compared with baseline. CP-900691 treatment reduced exogenous insulin requirements by approximately 25% (p < 0.04) while lowering plasma fructosamine from 2.87 +/- 0.09 to 2.22 +/- 0.17 mM (p < 0.05), indicative of improved glycemic control. There were no changes in any of the aforementioned parameters in the vehicle group. Because low HDLC and high triglycerides are well established risk factors for cardiovascular disease, the marked improvements in these parameters, and in glycemic control, body weight, and CRP, suggest that CP-900691 may be of benefit in diabetic and obese or hyperlipidemic populations.

Lecithin cholesterol acyl transferase (LCAT) deficiency is associated with low high-density lipoprotein (HDL) and the presence of an abnormal lipoprotein called lipoprotein X (Lp-X) that contributes to end-stage renal disease. We examined the possibility of using LCAT an as enzyme replacement therapy agent by testing the infusion of human recombinant (r)LCAT into several mouse models of LCAT deficiency. Infusion of plasma from human LCAT transgenic mice into LCAT-knockout (KO) mice rapidly increased HDL-cholesterol (C) and lowered cholesterol in fractions containing very-low-density lipoprotein (VLDL) and Lp-X. rLCAT was produced in a stably transfected human embryonic kidney 293f cell line and purified to homogeneity, with a specific activity of 1850 nmol/mg/h. Infusion of rLCAT intravenously, subcutaneously, or intramuscularly into human apoA-I transgenic mice showed a nearly identical effect in increasing HDL-C approximately 2-fold. When rLCAT was intravenously injected into LCAT-KO mice, it showed a similar effect as plasma from human LCAT transgenic mice in correcting the abnormal lipoprotein profile, but it had a considerably shorter half-life of approximately 1.23 ± 0.63 versus 8.29 ± 1.82 h for the plasma infusion. rLCAT intravenously injected in LCAT-KO mice crossed with human apolipoprotein (apo)A-I transgenic mice had a half-life of 7.39 ± 2.1 h and increased HDL-C more than 8-fold. rLCAT treatment of LCAT-KO mice was found to increase cholesterol efflux to HDL isolated from mice when added to cells transfected with either ATP-binding cassette (ABC) transporter A1 or ABCG1. In summary, rLCAT treatment rapidly restored the normal lipoprotein phenotype in LCAT-KO mice and increased cholesterol efflux, suggesting the possibility of using rLCAT as an enzyme replacement therapy agent for LCAT deficiency.

The synthesis of a new series of phenylpropanoic acid derivatives incorporating an heteroaryl group at the alpha-position and their evaluation for binding and activation of PPARalpha and PPARgamma are presented in this report. Among the new compounds, (S)-3-{4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-phenyl}-2-1,2,3-triazol-2-yl-propionic acid (17j), was identified as a potent human PPARalpha/gamma dual agonist (EC(50)=0.013 and 0.061 microM, respectively) with demonstrated oral bioavailability in rat and dog. 17j was shown to decrease insulin levels, plasma glucose, and triglycerides in the ZDF female rat model. In the human apolipoprotein A-1/CETP transgenic mouse model 17j produced increases in hApoA1 and HDL-C and decreases in plasma triglycerides. The increased potency for binding and activation of both PPAR subtypes observed with 17j when compared to previous analogs in this series was explained based on results derived from crystallographic and modeling studies.

Cholesterol absorption inhibition (CAI) represents an important treatment option for hypercholesterolemia. Herein, we report the design and evaluation of a series of substituted oxazolidinones as ligands for the Niemann Pick C1 Like 1 (NPC1L1) protein, a key mediator of cholesterol transport. Novel analogs were initially evaluated in a brush border membrane NPC1L1 binding assay; subsequently, promising compounds were evaluated in vivo for acute inhibition of cholesterol absorption. These studies identified analogs with low micromolar NPC1L1 binding affinity and acute in vivo efficacy of >50% absorption inhibition at 3mg/kg.

A new series of α-aryl or α-heteroarylphenyl propanoic acid derivatives was synthesized that incorporate acetylene-, ethylene-, propyl-, or nitrogen-derived linkers as a replacement of the commonly used ether moiety that joins the central phenyl ring with the lipophilic tail. The effect of these modifications in the binding and activation of PPARα and PPARγ was first evaluated in vitro. Compounds possessing suitable profiles were then evaluated in the ob/ob mouse model of type 2 diabetes. The propylene derivative 40 and the propyl derivative 53 demonstrated robust plasma glucose lowering activity in this model. Compound 53 was also evaluated in male Zucker diabetic fatty rats and was found to achieve normalization of glucose, triglycerides, and insulin levels. An X-ray crystal structure of the complex of 53 with the PPARγ-ligand-binding domain was obtained and discussed in this report.

4-Sulfamoyl pyrroles were designed as novel hepatoselective HMG-CoA reductase inhibitors (statins) to reduce myalgia, a statin-induced adverse effect. The compounds were prepared via a [3+2] cycloaddition of a Münchnone with a sulfonamide-substituted alkyne. We identified compounds with greater selectivity for hepatocytes compared to L6-myocytes than rosuvastatin and atorvastatin. There was an inverse correlation of myocyte potencies and ClogP values. A number of analogs were effective at reducing cholesterol in acute and chronic in vivo models but they lacked sufficient chronic in vivo activity to warrant further development.

In an effort to identify hepatoselective inhibitors of HMG-CoA reductase, two series of pyrroles were synthesized and evaluated. Efforts were made to modify (3R,5R)-7-[3-(4-fluorophenyl)-1-isopropyl-4-phenyl-5-phenylcarbamoyl-1H-pyrrol-2-yl]-3,5-dihydroxy-heptanoic acid sodium salt 30 in order to reduce its lipophilicity and therefore increase hepatoselectivity. Two strategies that were explored were replacement of the lipophilic 3-phenyl substituent with either a polar function (pyridyl series) or with lower alkyl substituents (lower alkyl series) and attachment of additional polar moieties at the 2-position of the pyrrole ring. One compound was identified to be both highly hepatoselective and active in vivo. We report the discovery, synthesis, and optimization of substituted pyrrole-based hepatoselective ligands as potent inhibitors of HMG-CoA reductase for reducing low density lipoprotein cholesterol (LDL-c) in the treatment of hypercholesterolemia.