Novel pyrrolidine heterocycles as CCR1 antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 18, 2010, Pages 5477-5479

  Merritt, J Robert ^a   James, Ray ^a   Paradkar, Vidyadhar M ^a   Zhang, Chongwu ^a   Liu, Ruiyan ^a   Liu, Jinqi ^a   Jacob, Biji ^a   Chiriac, Camelia ^a   Ohlmeyer, Michael J ^a   Quadros, Elizabeth ^a   Wines, Pamela ^a   Postelnek, Jennifer ^a   Hicks, Catherine M ^a   Chen, Weiqing ^a   Kimble, Earl F ^a   O'Brien, Linda ^a   White, Nicole ^a   Desai, Hema ^a   Appell, Kenneth C ^a   Webb, Maria L ^a  

^a Ligand Pharmaceuticals Inc   (United States)

Author keywords

CCL3; CCR1; Chemokine

Indexed keywords

1 [5 CHLORO 2 [2 [4 (4 FLUOROBENZYL) 2 METHYL 1 PIPERAZINYL] 2 OXOETHOXY]PHENYL]UREA; CHEMOKINE RECEPTOR ANTAGONIST; CHEMOKINE RECEPTOR CCR1; CP 481715; IMIDAZOLE DERIVATIVE; MACROPHAGE INFLAMMATORY PROTEIN 1ALPHA; PYRROLIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; BINDING COMPETITION; CELL LINE; CHEMOTAXIS; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG HALF LIFE; DRUG POTENCY; DRUG STRUCTURE; IC 50; LIVER MICROSOME; NONHUMAN; PROTEIN EXPRESSION; PROTEIN PROTEIN INTERACTION; RAT; TIME TO MAXIMUM PLASMA CONCENTRATION;

ANIMALS; CELL LINE; CHEMOKINE CCL3; CHEMOTAXIS; MICROSOMES, LIVER; PYRROLIDINES; RATS; RECEPTORS, CCR1; TRIAZOLES;

RATTUS;

EID: 77956172932     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.07.082     Document Type: Article

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19. 125I]-MIP1α (5 μl) was then added at final concentration of 0.1 nM. The plate was spun at 2500 rpm for 2 min and incubated for 4 h and read (1 min/well count time) on a MicroBeta® TriLux (Perkin-Elmer, USA).
20. 2-humidified incubator at 37 °C. After the incubation period, the migrating cells from the bottom chamber were quantified by transferring equal volumes of cells into cell titer-glo and read on Perkin-Elmer Victor™ multilable counter using luminescence protocol.
21. Rat and human liver microsome stability assays. Assay mixtures typically contained rat or human 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.
22. Pharmacokinetics studies in the rat. In preliminary screening studies, test compounds were dosed orally by gavage (5 mg/kg in 0.5% methyl cellulose) to 3-4 male Sprague-Dawley rats, either as single compounds or as part of a cassette. Serial blood samples were collected from an indwelling arterial cannula up to 6 or 24 h. For bioavailability studies, test compound (1 mg/kg) was also administered intravenously via an indwelling catheter. Plasma was separated and samples were prepared by protein precipitation and analyzed for parent compound by LC/MS/MS. Pharmacokinetic parameters were determined using non-compartmental analysis (WinNonlin, Pharsight Corp., Mountain View, CA).
23. 50 was determined by fitting the plot of percent inhibition versus logarithmic concentration values (μM).