Novel transient receptor potential vanilloid 1 receptor antagonists for the treatment of pain: structure-activity relationships for ureas with quinoline, isoquinoline, quinazoline, phthalazine, quinoxaline, and cinnoline moieties.

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.

• Authors: Arthur Gomtsyan, Erol K Bayburt, Robert G Schmidt, Guo Zhu Zheng, Richard J Perner, Stanley Didomenico, John R Koenig, Sean Turner, Tammie Jinkerson, Irene Drizin, Steven M Hannick, Bryan S Macri, Heath A McDonald, Prisca Honore, Carol T Wismer, Kennan C Marsh, Jill Wetter, Kent D Stewart, Tetsuro Oie, Michael F Jarvis, Carol S Surowy, Connie R Faltynek, Chih-Hung Lee
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 48 Issue 3 Pg. 744-52 (Feb 10 2005) ISSN: 0022-2623 [Print] United States
• PMID: 15689158 (Publication Type: Journal Article)

Chemical References

• Analgesics
• Heterocyclic Compounds, 2-Ring
• Isoquinolines
• N-isoquinolin-5-yl-N'-(4-trifluoromethylbenzyl)urea
• Quinazolines
• Quinolines
• Receptors, Drug
• Urea
• cinnoline
• Calcium

Topics

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