Abstract:
:Based upon a previously reported lead compound 1, a series of 1,2-diamino-ethane-substituted-6,7,8,9-tetrahydro-5H-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.
journal_name
Bioorg Med Chem Lettjournal_title
Bioorganic & medicinal chemistry lettersauthors
Lebsack AD,Rech JC,Branstetter BJ,Hawryluk NA,Merit JE,Allison B,Rynberg R,Buma J,Rizzolio M,Swanson N,Ao H,Maher MP,Herrmann M,Freedman J,Scott BP,Luo L,Bhattacharya A,Wang Q,Chaplan SR,Wickenden AD,Breitenbucherdoi
10.1016/j.bmcl.2010.09.006subject
Has Abstractpub_date
2010-12-01 00:00:00pages
7142-6issue
23eissn
0960-894Xissn
1464-3405pii
S0960-894X(10)01297-7journal_volume
20pub_type
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