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J Med Chem ; 48(3): 744-52, 2005 Feb 10.
Article in English | MEDLINE | ID: mdl-15689158

ABSTRACT

Novel transient receptor potential vanilloid 1 (TRPV1) receptor antagonists with various bicyclic heteroaromatic pharmacophores were synthesized, and their in vitro activity in blocking capsaicin activation of TRPV1 was assessed. On the basis of the contribution of these pharmacophores to the in vitro potency, they were ranked in the order of 5-isoquinoline > 8-quinoline = 8-quinazoline > 8-isoquinoline > or = cinnoline approximately phthalazine approximately quinoxaline approximately 5-quinoline. The 5-isoquinoline-containing compound 14a (hTRPV1 IC50 = 4 nM) exhibited 46% oral bioavailability and in vivo activity in animal models of visceral and inflammatory pain. Pharmacokinetic and pharmacological properties of 14a are substantial improvements over the profile of the high-throughput screening hit 1 (hTRPV1 IC50 = 22 nM), which was not efficacious in animal pain models and was not orally bioavailable.


Subject(s)
Analgesics/chemical synthesis , Isoquinolines/chemical synthesis , Pain/drug therapy , Receptors, Drug/antagonists & inhibitors , Urea/analogs & derivatives , Urea/chemical synthesis , Abdominal Pain/drug therapy , Administration, Oral , Analgesics/chemistry , Analgesics/pharmacology , Animals , Biological Availability , Calcium/metabolism , Cells, Cultured , Disease Models, Animal , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/pharmacology , Humans , Hyperalgesia/drug therapy , Isoquinolines/chemistry , Isoquinolines/pharmacology , Models, Molecular , Quinazolines/chemical synthesis , Quinazolines/chemistry , Quinazolines/pharmacology , Quinolines/chemical synthesis , Quinolines/chemistry , Quinolines/pharmacology , Rats , Static Electricity , Structure-Activity Relationship , Urea/chemistry , Urea/pharmacology
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