Details

Autor(en) / Beteiligte

• Lebsack, Alec D.
• Rech, Jason C.
• Branstetter, Bryan J.
• Hawryluk, Natalie A.
• Merit, Jeffrey E.
• Allison, Brett
• Rynberg, Raymond
• Buma, Johnathan
• Rizzolio, Michele
• Swanson, Nadia
• Ao, Hong
• Maher, Michael P.
• Herrmann, Michelle
• Freedman, Jamie
• Scott, Brian P.
• Luo, Lin
• Bhattacharya, Anindya
• Wang, Qi
• Chaplan, Sandra R.
• Wickenden, Alan D.
• Breitenbucher, J. Guy

Titel

1,2-Diamino-ethane-substituted-6,7,8,9-tetrahydro-5 H-pyrimido[4,5- d]azepines as TRPV1 antagonists with improved properties

Ist Teil von

• Bioorganic & medicinal chemistry letters, 2010, Vol.20 (23), p.7142-7146

Ort / Verlag

Elsevier Ltd

Erscheinungsjahr

2010

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• A series of 1,2-diamino-ethane-substituted-6,7,8,9-tetrahydro-5 H-pyrimido[4,5- d]azepines were synthesized and evaluated for improved physiochemical and pharmacokinetic properties while maintaining TRPV1 antagonist activity. Based upon a previously reported lead compound 1, a series of 1,2-diamino-ethane-substituted-6,7,8,9-tetrahydro-5 H-pyrimido[4,5- d]azepines were synthesized and evaluated for improved physiochemical and pharmacokinetic properties while maintaining TRPV1 antagonist activity. Structure–activity relationship studies directed toward improving the aqueous solubility (pH 2 and fasted-state simulated intestinal fluid (SIF)) and rat pharmacokinetics led to the discovery of compound 13. Aqueous solubility of compound 13 (pH 2 = >237 μg/mL and SIF = 11 μg/mL) was significantly improved over compound 1 (pH 2 = 5 μg/mL and SIF = 0.5 μg/mL). In addition, compound 13 afforded improved rat pharmacokinetics (CL = 0.7 L/kg/h) compared to compound 1 (CL = 3.1 L/kg/h). Compound 13 was orally bioavailable and afforded a significant reversal of carrageenan-induced thermal hyperalgesia at 5 and 30 mg/kg in rats.