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John P Gibbs, Maurice G Emery,
Ian McCaffery,
Brian Smith,
Megan A Gibbs,
Anna Akrami,
John Rossi,
Katherine Paweletz,
Marc R Gastonguay,
Edgar Bautista,
Minghan Wang,
Riccardo Perfetti,
Oranee Daniels
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ABSTRACT: Inhibition of 11β-HSD1 is hypothesized to improve measures of insulin sensitivity and hepatic glucose output in patients with type II diabetes. AMG 221 is a potent, small molecule inhibitor of 11β-HSD1. The objective of this analysis is to describe the pharmacokinetic/pharmacodynamic (PK/PD) relationship between AMG 221 and 11β-HSD1 inhibition in ex vivo adipose tissue samples. Healthy, obese subjects were administered a single dose of 3, 30, or 100 mg of oral AMG 221 (n = 44) or placebo (n = 11). Serial blood samples were collected over 24 hours. Subcutaneous adipose tissue samples were collected by open biopsy. Population PK/PD analysis was conducted using NONMEM. The inhibitory effects (mean ± standard error of the estimate) of AMG 221 on 11β-HSD1 activity were directly related to adipose concentrations with I(max) (the maximal inhibition of 11β-HSD1 activity) and IC₅₀ (the plasma AMG 221 concentration associated with 50% inhibition of enzyme activity) of 0.975 ± 0.003 and 1.19 ± 0.12 ng/mL, respectively. The estimated baseline 11β-HSD1 enzyme activity was 755 ± 61 pmol/mg. An equilibration rate constant (k(eo)) of 0.220 ± 0.021 h⁻¹ described the delay between plasma and adipose tissue AMG 221 concentrations. AMG 221 potently blocked 11β-HSD1 activity, producing sustained inhibition for the 24-hour study duration as measured in ex vivo adipose samples. Early characterization of concentration-response relationships can support rational selection of dose and regimen for future studies.
The Journal of Clinical Pharmacology 06/2011; 51(6):830-41. · 2.91 Impact Factor
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Murielle M Véniant,
Clarence Hale,
Randall W Hungate,
Kyung Gahm, Maurice G Emery,
Janan Jona,
Smriti Joseph,
Jeffrey Adams,
Andrew Hague,
George Moniz, [......],
Michelle M Chen,
Rod Cupples,
Ki Won Kim,
David J St Jean,
Lars Johansson,
Martin A Henriksson,
Meredith Williams,
Jerk Vallgårda,
Christopher Fotsch,
Minghan Wang
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ABSTRACT: Thiazolones with an exo-norbornylamine at the 2-position and an isopropyl group on the 5-position are potent 11beta-HSD1 inhibitors. However, the C-5 center was prone to epimerization in vitro and in vivo, forming a less potent diastereomer. A methyl group was added to the C-5 position to eliminate epimerization, leading to the discovery of (S)-2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (AMG 221). This compound decreased fed blood glucose and insulin levels and reduced body weight in diet-induced obesity mice.
Journal of Medicinal Chemistry 06/2010; 53(11):4481-7. · 4.80 Impact Factor
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ABSTRACT: A goal of preclinical discovery is the identification of drug candidates suitable for clinical testing. Successful integration of in vitro and in vivo experimental data sets can afford projections of human dose regimens anticipated to be safe and therapeutically beneficial. While in vitro experiments guide new chemical syntheses and are essential to understanding drug action and disposition, in vivo characterizations provide unique insight into complex biological systems that control concentrations at the site of action and pharmacologic response. Pharmacokinetic and pharmacodynamic (PK/PD) concepts underlying drug disposition and response provide a quantitative framework with which to identify potential clinical candidates. To improve throughput in earlier stages of drug discovery, in vivo pharmacokinetic study designs such as cassette dosing and sparse sampling schemes have been utilized. In later stages of discovery, pharmacokinetic studies using chemical inhibitors or surgical and genetic animal models are used to characterize the underlying determinants of drug disposition. In a complimentary fashion, modeling of in vivo pharmacodynamic effects may quantitatively link biomarkers to pharmacological response, validate in vitro to in vivo correlations and underwrite predictions of efficacious exposure targets. When applied to in vivo discovery data, PK/PD models have aided in understanding mechanisms of pharmacological response such as receptor theory in the central nervous system and cell turnover concepts in infectious disease and oncology. This review considers the role of in vivo testing toward understanding the pharmacokinetic and pharmacodynamic attributes of lead candidates in drug discovery.
Combinatorial chemistry & high throughput screening 02/2010; 13(2):207-18. · 2.46 Impact Factor
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David N Hovland,
Robert B Boyd,
Mark T Butt,
Jeffery A Engelhardt,
Michael S Moxness,
Mark H Ma, Maurice G Emery,
Nadia B Ernst,
Randall P Reed,
Jillynne R Zeller,
Don M Gash,
Donna M Masterman,
Beth M Potter,
Mary E Cosenza,
Ruth M Lightfoot
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ABSTRACT: Recombinant human glial cell line-derived neurotrophic factor (r-metHuGDNF) is a potent neuronal growth and survival factor that has been considered for clinical use in the treatment of Parkinson's disease (PD). Here we present results of a 6-month toxicology study in rhesus monkeys conducted to support clinical evaluation of chronic intraputamenal infusion of r-metHuGDNF for PD. Monkeys (6-9/sex/group) were treated with 0 (vehicle), 15, 30, or 100 microg/day r-metHuGDNF by continuous unilateral intraputamenal infusion (150 microl/day flow rate) for 6 months; a subset of animals (2-3/sex/group) underwent a subsequent 3-month treatment-free recovery period. Notable observations included reduced food consumption and body weight at 100 microg/day and meningeal thickening underlying the medulla oblongata and/or overlying various spinal cord segments at 30 and 100 microg/day. In addition, multifocal cerebellar Purkinje cell loss (with associated atrophy of the molecular layer and, in some cases, granule cell loss) was observed in 4 monkeys in the 100-microg/day group. This cerebellar finding has not been observed in previous nonclinical studies evaluating r-metHuGDNF. The small number of affected animals precludes definitive conclusions regarding the pathogenesis of the cerebellar lesion, but the data support an association with r-metHuGDNF treatment.
Toxicologic Pathology 02/2007; 35(7):1013-29. · 1.91 Impact Factor
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ABSTRACT: Previous studies suggest that hepatic cytochrome P450 2E1 (CYP2E1) activity is increased in individuals with chronic alcoholism, nonalcoholic steatohepatitis (NASH), and morbid obesity, and may contribute to liver disease. We studied 16 morbidly obese subjects with varying degrees of hepatic steatosis and 16 normal-weight controls. Obese subjects were evaluated at baseline, 6 weeks, and 1 year after gastroplasty, a procedure that leads to weight loss. Hepatic CYP2E1 activity was assessed by determination of the clearance of chlorzoxazone (CLZ), an in vivo CYP2E1-selective probe. Liver biopsy tissue was obtained during surgery for histopathology. Both the total and unbound oral CLZ clearance (Cl(u)/F) was elevated approximately threefold in morbidly obese subjects compared with controls (P <.001). The Cl(u)/F was significantly higher among subjects with steatosis involving >50% of hepatocytes, compared with those with steatosis in < or =50% of hepatocytes (P =.02). At postoperative week 6 and year 1, the median body mass index (BMI) of subjects who underwent gastroplasty decreased by 11% and 33%, total oral CLZ clearance declined by 16% (P <.01) and 46% (P <.05), and Cl(u)/F decreased by 18% (P <.05) and 35% (P =.16), respectively. Moreover, those subjects with a year 1 BMI <30 kg/m(2) exhibited a median Cl(u)/F that was 63% lower (P =.02) than the respective clearance for all other subjects. In conclusion, hepatic CYP2E1 activity is up-regulated in morbidly obese subjects. A positive association between the degree of steatosis and CYP2E1 activity preoperatively and between the extent of obesity and CYP2E1 activity postoperatively, suggests that CYP2E1 induction is related to or caused by hepatic pathology that results from morbid obesity.
Hepatology 09/2003; 38(2):428-35. · 11.66 Impact Factor
