Tetrahydro-naphthols as orally available TRPV1 inhibitors

Starting from a naphthol-based lead series with low oral bioavailability, we have identified potent TRPV1 antagonists with oral bioavailability in rats. These compounds emerged from SAR studies aimed at replacing the lead’s phenol structure whilst maintaining potency. Compound rac-6a is an orally av...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2012-05, Vol.22 (10), p.3408-3411
Hauptverfasser:	Urbahns, Klaus, Yura, Takeshi, Gupta, Jang B., Tajimi, Masaomi, Fujishima, Hiroshi, Masuda, Tsutomu, Yamamoto, Noriyuki, Ikegami, Yuka, Marumo, Makiko, Yasoshima, Kayo, Yoshida, Nagahiro, Moriwaki, Toshiya, Madge, David, Chan, Fiona, Mogi, Muneto
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Animals antagonists bioavailability Biological and medical sciences Biological Availability enantiomers Medical sciences Naphthols Naphthols - administration & dosage Naphthols - pharmacokinetics Naphthols - pharmacology Oral bioavailability Pharmacology. Drug treatments phenol Rats Rats, Sprague-Dawley TRPV Cation Channels - antagonists & inhibitors TRPV1 Urinary incontinence Vanilloid receptor antagonist
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Beschreibung
Zusammenfassung:	Starting from a naphthol-based lead series with low oral bioavailability, we have identified potent TRPV1 antagonists with oral bioavailability in rats. These compounds emerged from SAR studies aimed at replacing the lead’s phenol structure whilst maintaining potency. Compound rac-6a is an orally available TRPV1 antagonist with single-digit nanomolar activity. The enantiomers show a low eudismic ratio at the receptor level.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2012.03.108