Activation..... supplementary

Activation..... supplementary - Activation of mGlu2/3...

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Unformatted text preview: Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: results from a randomized Phase 2 clinical trial Sandeep T. Patil, Lu Zhang, Ferenc Martenyi, Stephen L. Lowe, Kimberley A. Jackson, Boris V. Andreev, Alla S. Avedisova, Leonid M. Bardenstein, Issak Y. Gurovich, Margarita A. Morozova, Sergey N Mosolov, Nokolai G. Neznanov, Alexander M Reznik, Anatoly B. Smulevich and Vladimir A Tochilov, James A. Monn, Bryan G. Johnson, and Darryle D. Schoepp Supplementary Table 1 Affinity of LY404039 versus the prodrug compound LY2140023 for recombinant human and native rat brain mGlu2/3 receptors Displacement of 3 H − LY341495 a binding (K i , nM) (mean + s.e.m., n = 3) Receptor Preparation LY404039 LY2140023 (Methionine – LY404039) Human mGlu2 231 + 47 > 100,000 Human mGlu3 45 + 7 > 100,000 Rat Forebrain 93 + 23 > 100,000 a LY341495 is an mGlu2/3 antagonist S H H NH 2 HO 2 C COOH O O S H H N H HO 2 C COOH O O O NH 2 S Time After Last Dose (hr) 4 8 12 16 20 24 LY2140023 or LY404039 Mean Plasma Concentration (ng/mL) 50 100 150 200 250 300 LY2140023 LY404039 Supplementary Figure 1 LY2140023 and LY404039 pharmacokinetics in human plasma: mean (standard deviation) plasma concentration time profiles for prodrug (LY2140023) and the active moiety (LY404039) following administration of 40 mg bid of LY2140023 for 7 days in healthy male volunteers (Study H8Y − LC − HBBB). Absorption of LY2140023 and conversion into LY404039 was rapid as demonstrated by measurable plasma concentrations at the first sampling time point (0.5 hours) for both analytes. The exposure to LY2140023 was approximately 30% of the exposure to LY404039 based on the molar ratio for both analytes calculated from AUC(0 −∞ ) parameters. Geometric mean estimates of t 1/2 for LY2140023 were 1.56 and 1.86 hours for LY2140023 and LY404039, respectively, following the first 40 − mg dose. Supplementary Table 2 Patient baseline demographic characteristics, severity of illness scores, extrapyramidal symptom scores, patient disposition, and discontinuations associated with adverse events or death Characteristic LY2140023 ( n = 98) Placebo ( n = 63) Olanzapine ( n = 34) Overall P − Value Demographic characteristics Age (mean years ± s.d.) 39.6 ± 14.4 41.0 ± 14.1 42.3 ± 13.0 0.59 Gender Male (%) 79.6 77.8 73.5 0.74 Origin Caucasian (%) 100.0 98.4 100.0 0.50 East Asia (%) 0.0 1.6 0.0 Weight (mean kg ± s.d.) 73.4 ± 12.2 74.1 ± 12.7 74.8 ± 12.3 0.85 BMI (mean kg/cm 2 ± s.d.) 24.1 ± 3.5 24.4 ± 3.3 25.1 ± 3.3 0.34 Smoking Status Yes (%) 58.2 66.7 64.7 0.54 Drinking Status Yes (%) 17.3 22.2 17.6 0.74 Patient Option Option 1 (%) 5.1 3.2 5.9 0.82 Option 2 (%) 94.9 96.8 94.1 Baseline severity of illness scores – mean (s.d.) PANSS − total 95.5 ± 11.4 93.8 ± 10.5 94.5 ± 12.9 0.63 PANSS − positive 24.0 ± 4.0 24.0 ± 3.8 24.4 ± 4.3 0.86 PANSS − negative 26.3 ± 4.0 25.4 ± 4.0 25.5 ± 4.1 0.39 CGI − Severity 4.9 ± 0.6 4.9 ± 0.6 4.8 ± 0.6 0.59 Baseline extrapyramidal symptom scores – mean (s.d.)Baseline extrapyramidal symptom scores – mean (s....
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This note was uploaded on 05/28/2010 for the course WE CHMOBI0000 taught by Professor Geertvanloo during the Spring '10 term at Ghent University.

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Activation..... supplementary - Activation of mGlu2/3...

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