The discovery of novel indole-2-carboxamides as cannabinoid CB1 receptor antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 1, 2011, Pages 497-501

  Cowley, Phillip M ^a   Baker, James ^a   Barn, David R ^a   Buchanan, Kirsteen I ^a   Carlyle, Ian ^a   Clark, John K ^a   Clarkson, Thomas R ^a   Deehan, Maureen ^a   Edwards, Darren ^a   Goodwin, Richard R ^a   Jaap, David ^a   Kiyoi, Yasuko ^a   Mort, Chris ^a   Palin, Ronald ^a   Prosser, Alan ^a   Walker, Glenn ^a   Ward, Nick ^a   Wishart, Grant ^a   Young, Trevor ^a  

^a MSD   (United Kingdom)

Author keywords

Antagonist; Cannabinoid; CB1; Indole

Indexed keywords

4 [6 METHOXY 2 (4 METHOXYPHENYL) 3 BENZOFURANYLCARBONYL]BENZONITRILE; CANNABINOID 1 RECEPTOR; CANNABINOID 1 RECEPTOR ANTAGONIST; INDOLE 2 CARBOXAMIDE DERIVATIVE; RIMONABANT; UNCLASSIFIED DRUG;

ARTICLE; CHO CELL; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG RECEPTOR BINDING; DRUG SYNTHESIS; HYPOTHERMIA; LIPOPHILICITY; MAXIMUM PLASMA CONCENTRATION; NONHUMAN; STRUCTURE ACTIVITY RELATION;

AMIDES; ANIMALS; DOGS; DRUG EVALUATION, PRECLINICAL; INDOLES; MALE; MICE; MODELS, MOLECULAR; RATS; RATS, WISTAR; RECEPTOR, CANNABINOID, CB1; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 78650514170     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.10.104     Document Type: Article

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12. The antagonist or vehicle (5% mulgofen in saline, 10 mL/kg) was administered po 75 min before rectal temperature was measured. WIN 55,212-2 mesylate (10 μmol/kg, 10 mL/kg) was administered s.c. 60 min prior to the rectal temperature measurement. The 60 min pre-treatment with WIN 55,212-2 mesylate corresponded to the maximal hypothermia attained by this agonist. Rectal temperature was measured using a metal probe with a Fluke 51K/J Thermometer. The probe was covered in a lubricant (vaseline) and was inserted approximately 1.5 cm into the rectum. The highest temperature stable for 10 s was recorded. Following completion of the test animals were humanely terminated.
13. + channel was determined by their ability to displace tritiated dofetilide in membrane homogenates from HEK-293 cells expressing the hERG channel.
14. 3): δ 8.02 (d, J = 1.5 Hz, 1H), 7.48 (dd, J = 1.5 and 8.5 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.05 (dd, J = 8.5 and 2.5 Hz, 1H), 7.01 (s, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.81 (br t, J = 6.0 Hz, 1H), 6.28 (d, J = 2.5 Hz, 1H), 5.82 (s, 2H), 3.89 (s, 3H), 3.27 (d, J = 6.5 Hz, 2H), 3.24 (t, J = 6.5 Hz, 1H), 3.13 (d, J = 6.5 Hz, 2H), 0.90 (s, 6H). Elemental analysis: measured C, 60.71; H, 5.16; N, 8.77; F, 11.48. Theory C, 60.63; H, 5.09; N, 8.84; F, 11.99.