Substituted chromones and quinolones as potent melanin-concentrating hormone receptor 1 antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 16, 2006, Pages 4237-4242

  Dyck, Brian ^a   Zhao, Liren ^a   Tamiya, Junko ^a   Pontillo, Joseph ^a   Hudson, Sarah ^a   Ching, Brett ^a   Heise, Christopher E ^a   Wen, Jenny ^a   Norton, Christi ^a   Madan, Ajay ^a   Schwarz, David ^a   Wade, Warren ^a   Goodfellow, Val S ^a  

^a NEUROCRINE BIOSCIENCES INC   (United States)

Author keywords

Anorectic; Anxiety; Depression; GPCR; MCH; Obesity

Indexed keywords

CHROMONE DERIVATIVE; HORMONE RECEPTOR BLOCKING AGENT; MELANIN; QUINOLONE DERIVATIVE;

ANIMAL EXPERIMENT; ARTICLE; BINDING AFFINITY; BIOAVAILABILITY; DRUG BINDING; DRUG SYNTHESIS; HUMAN; HUMAN CELL; NONHUMAN; RAT; SUBSTITUTION REACTION;

ADMINISTRATION, ORAL; ANIMALS; CHEMISTRY, PHARMACEUTICAL; CHROMONES; DRUG DESIGN; HUMANS; MELANINS; MICROSOMES, LIVER; MODELS, CHEMICAL; QUINOLONES; RATS; RECEPTORS, PITUITARY HORMONE; TIME FACTORS;

EID: 33745699186     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.05.075     Document Type: Article

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42. The pharmacokinetics and blood-brain barrier (BBB) penetrations were determined in male Sprague-Dawley rats following an intravenous (iv, N = 3/time point) and oral (po, N = 3/time point) dose. The dosing solution was prepared in purified water and filtered through a 0.2 μm nylon filter before administration (2 mL/kg) via tail vein (iv) or a gavage (po). Blood and brain tissue samples were taken at pre-determined time for composite sampling. All plasma and tissue samples were flash-frozen in liquid nitrogen within 10 min of sampling and stored in -70 °C or below until analysis. The bioanalytical method applied for the measurement of test articles in plasma along with added internal standard consisted of precipitation with 200 μL of acetonitrile from 50 μL of plasma, centrifugation and recovery of the supernatant, drying down in vacuum then reconstitution in acetonitrile-water solutions before introducing into an LC-MS/MS system for analysis. The lower limit of quantification (LLOQ) for the analytical methods was 5 ng/mL of test article in plasma. The bioanalytical method applied for the measurement of test articles in brain tissue along with added internal standard consisted of homogenizing half of the brain tissue (longitude cut) in 2 mL of acetonitrile/water (50:50), centrifugation and recovery of the supernatant before introducing into an LC-MS/MS system for analysis. LLOQ for the analytical methods was 5 ng/g of test article in brain tissue. All pharmacokinetic parameters were calculated from a non-compartmental model in WinNonlin program. Brain to plasma ratio was obtained by comparing brain AUC to plasma AUC.