Difluoroethylamines as an amide isostere in inhibitors of cathepsin K

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 3, 2011, Pages 920-923

  Isabel, Elise ^a   Mellon, Christophe ^a   Boyd, Michael J ^a   Chauret, Nathalie ^a   Deschênes, Denis ^a   Desmarais, Sylvie ^a   Falgueyret, Jean Pierre ^a   Gauthier, Jacques Yves ^a   Khougaz, Karine ^a   Lau, Cheuk K ^a   Léger, Serge ^a   Levorse, Dorothy A ^b   Li, Chun Sing ^a   Massé, Frédéric ^a   David Percival, M ^a   Roy, Bruno ^a   Scheigetz, John ^a   Thérien, Michel ^a   Truong, Vouy Linh ^a   Wesolowski, Gregg ^b   Young, Robert N ^a   Zamboni, Robert ^a   Cameron Black, W ^a   more..

^a MERCK FROSST CENTRE FOR THERAPEUTIC RESEARCH   (Canada)

^b MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Cat K; Cathepsin K; Difluoroethylamine; log D; pKa

Indexed keywords

AMIDE; CATHEPSIN K INHIBITOR; DIFLUOROETHYLAMINE DERIVATIVE; L 873724; ODANACATIB; TRIFLUOROETHYLAMINE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; DRUG BIOAVAILABILITY; DRUG POTENCY; IC 50; NONHUMAN; PKA; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; AMIDES; ANIMALS; BIPHENYL COMPOUNDS; CATHEPSIN K; DOGS; ETHYLAMINES; PROTEASE INHIBITORS; RATS;

EID: 78751649521     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.12.070     Document Type: Article

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10. Solubility measurements: Equilibrium solubility measurements were carried out by stirring the compounds, prepared at a concentration range of 5-10 mg/mL in water for 16 h at room temperature in the absence of light. The supernatant was recovered by centrifugation (15,000 rpm) and the excess solids were recovered for X-ray powder diffraction analysis. Solubility measurements were determined by HPLC. X-ray powder diffraction: XRPD patterns were measured using a Bruker Discover D8, Vantec-1 PSD detector, Cu Kα source at a generator power of 35 kV and 45 mA. A detector-scan continuous mode scan (transmission mode) was used with a range of 5-40° 2θ with a step size of 0.014° and 0.2 s time per step. The step time was 351 s (23 min total run time). The samples were measured on a kapton plate.
11. a values were calculated using RefinementPro v.2.2 software.
12. 7.0 value of API from the measured retention time by the HPLC/DAD analysis of the 100 μM standard solution.
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15. 2O.
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17. 50. This corrects for the difference between rabbit and human potencies.