The discovery of biaryl carboxamides as novel small molecule agonists of the motilin receptor

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 24, 2008, Pages 6429-6436

  Westaway, Susan M ^a   Brown, Samantha L ^a   Conway, Elizabeth ^a   Heightman, Tom D ^a   Johnson, Christopher N ^a   Lapsley, Kate ^a   Macdonald, Gregor J ^a   MacPherson, David T ^a   Mitchell, Darren J ^a   Myatt, James W ^a   Seal, Jon T ^a   Stanway, Steven J ^a   Stemp, Geoffrey ^a   Thompson, Mervyn ^a   Celestini, Paolo ^b   Colombo, Andrea ^b   Consonni, Alessandra ^b   Gagliardi, Stefania ^b   Riccaboni, Mauro ^b   Ronzoni, Silvano ^b   Briggs, Michael A ^a   Matthews, Kim L ^a   Stevens, Alexander J ^a   Bolton, Victoria J ^a   Boyfield, Izzy ^a   Jarvie, Emma M ^a   Stratton, Sharon C ^a   Sanger, Gareth J ^a   more..

^a GLAXOSMITHKLINE   (United Kingdom)

^b NiKem Research   (Italy)

Author keywords

Motilin; Motilin receptor agonist

Indexed keywords

AMIDE; GASTROINTESTINAL AGENT; MEMBRANE RECEPTOR; MOTILIN RECEPTOR; MOTILIN RECEPTOR AGONIST; POLYCYCLIC AROMATIC HYDROCARBON DERIVATIVE; PROKINETIC AGENT; PYRIDINE DERIVATIVE; UNCLASSIFIED DRUG; UREA;

ANIMAL CELL; ARTICLE; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG POTENCY; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; NONHUMAN; PHYSICAL CHEMISTRY; RABBIT; STOMACH ANTRUM; STRUCTURE ACTIVITY RELATION;

ANIMALS; CARBON; CHEMISTRY, PHARMACEUTICAL; DRUG DESIGN; GASTRINS; HUMANS; INHIBITORY CONCENTRATION 50; KINETICS; MODELS, CHEMICAL; PYRIDINES; RABBITS; RATS; RECEPTORS, GASTROINTESTINAL HORMONE; RECEPTORS, NEUROPEPTIDE;

ORYCTOLAGUS CUNICULUS;

EID: 56249132980     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.10.072     Document Type: Article

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27. 50 values represent the mean from at least 3 independent experiments with SEM ≤ 0.2 (SD ≤ 0.3) in all cases except compound (25) where SEM = 0.2 (SD = 0.4, n = 5) and compounds (8), (10), (24), (31), (35), (44) and (47) where n = 2. Comparison of activities of standard compounds in these assay formats:{A table is presented}
28. FLIPR assay protocol: HEK-293 cells stably expressing the human motilin receptor were seeded (30,000 cells/100 μL growth media/well) into poly-d-lysine coated 96-well black-wall, clear-bottom microtitre plates (Corning) 24 h prior to assay. On the day of assay the cells were loaded with 2 μΜ (final) Fluo-4-AM fluorescent indicator dye (Molecular Probes) and 1 mM (final) probenicid in assay buffer (145 mM sodium chloride, 2.5 mM potassium chloride, 10 mM Hepes, 10 mM glucose, 1.2 mM magnesium chloride, 1.5 mM calcium chloride and 0.1% BSA) (50 μL loading solution added to each well). Plates were incubated for 1 h at 25 °C, before being washed four times with 100 μL assay buffer using the EMBLA cell washer; 150 μL residual being left after the final wash. The cells were then incubated at 25 °C for 20 min and the plates were then assayed on a Fluorometric Imaging Plate Reader (FLIPR, Molecular Devices). Test compounds were prepared in assay buffer without probenecid. In the FLIPR, 50 μL of test compound was added to the cells and changes in fluorescence measured over a 2-min timeframe. Maximum change in fluorescence over baseline was used to determine agonist response and concentration response curves were constructed, using a 4-parameter logistic equation. All compounds were full agonists in this assay.
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39. +).