Identification and hit-to-lead optimization of a novel class of CB1 antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 18, 2010, Pages 5449-5453

  Letourneau, Jeffrey J ^a   Jokiel, Patrick ^a   Olson, John ^a   Riviello, Christopher M ^a   Ho, Koc Kan ^a   McAleer, Lihong ^a   Yang, Jingchun ^a   Swanson, Robert N ^a   Baker, James ^b   Cowley, Phillip ^b   Edwards, Darren ^b   Ward, Nick ^b   Ohlmeyer, Michael H J ^a   Webb, Maria L ^a  

^a Ligand Pharmaceuticals Inc   (United States)

^b MSD   (United Kingdom)

Author keywords

Antagonist; Benzimidazole; Cannabinoid; CB1; GPCR; Indole; Inverted indole; Obesity

Indexed keywords

2,3 DIHYDRO 5 METHYL 3 (MORPHOLINOMETHYL) 6 (1 NAPHTHOYL)PYRROLO[1,2,3 DE][1,4]BENZOXAZINE; BENZIMIDAZOLE; CANNABINOID 1 RECEPTOR ANTAGONIST; RIMONABANT;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; AQUEOUS SOLUTION; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG HALF LIFE; DRUG IDENTIFICATION; DRUG SCREENING; DRUG SOLUBILITY; DRUG SYNTHESIS; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN CELL; HYPOTHERMIA; IN VIVO STUDY; LIVER MICROSOME; MALE; NONHUMAN; OBESITY; RAT; STRUCTURE ACTIVITY RELATION;

ANIMALS; BENZIMIDAZOLES; HUMANS; HYPOTHERMIA; INDOLES; MALE; MICE; MICROSOMES, LIVER; OBESITY; RATS; RATS, WISTAR; RECEPTOR, CANNABINOID, CB1; SOLUBILITY; STRUCTURE-ACTIVITY RELATIONSHIP;

RATTUS;

EID: 77956170677     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.07.091     Document Type: Article

References (23)

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17. -6 M CP-55940 in DMEM/F12 without BSA were added to all wells of the assay plate. After 5 h at 37 °C, detection was performed by adding 100 μL/well Bright-Glo, incubating the assay plate at RT for a further 5 min and counting for 0.5 s/well in a Wallac Microbeta Trilux.
18. 50 values of 20 nM, 13 nM and 8 nM, respectively, in the CB1 binding assay.
19. Liver microsome stability assays were performed as follows: Assay mixtures typically contained human or mouse microsomes (300 nM cytochrome P450, BD Gentest, Woburn, MA), phosphate buffer (pH 7.4), 1 μM test compound, 1 mM NADPH in a final assay volume of 0.1 mL. Incubations were for 30 min at 37 °C and were terminated by the addition of 0.2 ml of acetonitrile. Samples were centrifuged at 2000g and analyzed by LC/MS. The percentage of compound remaining at 30 min was calculated.
20. Aqueous solubilities were determined using a medium-throughput adaptation of a shake-flask methodology. A 10 mM solution of the test compound in DMSO was added to 0.05 M phosphate buffered saline pH 7.4 such that the final concentration of DMSO was 2%. The resultant mixture was then vortex mixed (1500 rpm) for 24 ± 0.5 h at 21 ± 2 °C. After mixing, the resultant solution/suspension was filtered under vacuum using a filter plate (Millipore Multiscreen HTS, 0.4 μM). The concentration of the compound in the filtrate was determined by High Performance Liquid Chromatography (HPLC) running a generic acid gradient method with UV detection at 230 nm. Peak areas from analysis of the diluted filtrates were quantified by comparison to a calibration line prepared by injecting onto the HPLC three different volumes of a 50 μM solution of the test compound in DMSO. Solubilities were determined in duplicate for each test compound and average values reported.
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22. WIN 55,212-2 induced hypothermia test. The antagonist or vehicle (5% mulgofen in saline, 10 ml/kg) was administered sc 75 min before rectal temperature was measured. WIN 55,212-2 mesylate (10 μmol/kg, 10 ml/kg) was administered sc 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 51 K/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.
23. Compound 18c and other compounds from this series were demonstrated to have significantly lower affinity at the mouse CB1 receptor versus the human CB1 receptor. For example, compound 18c was found to be ∼14-fold less potent at the mouse CB1 receptor than at the human CB1 receptor as determined in a mouse brain membrane binding displacement assay (unpublished data).