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.
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.
Gomtsyan
Arthur
A
Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. arthur.r.gomtsyan@abbott.com
Bayburt
Erol K
EK
Schmidt
Robert G
RG
Zheng
Guo Zhu
GZ
Perner
Richard J
RJ
Didomenico
Stanley
S
Koenig
John R
JR
Turner
Sean
S
Jinkerson
Tammie
T
Drizin
Irene
I
Hannick
Steven M
SM
Macri
Bryan S
BS
McDonald
Heath A
HA
Honore
Prisca
P
Wismer
Carol T
CT
Marsh
Kennan C
KC
Wetter
Jill
J
Stewart
Kent D
KD
Oie
Tetsuro
T
Jarvis
Michael F
MF
Surowy
Carol S
CS
Faltynek
Connie R
CR
Lee
Chih-Hung
CH
D015746:Abdominal Pain / Q000188:drug therapy; D000284:Administration, Oral; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D010146:Pain / Q000188:drug therapy*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011955:Receptors, Drug / Q000037:antagonists & inhibitors*; D055672:Static Electricity; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000700:Analgesics; D006574:Heterocyclic Compounds, 2-Ring; D007546:Isoquinolines; C497147:N-isoquinolin-5-yl-N'-(4-trifluoromethylbenzyl)urea; D011799:Quinazolines; D011804:Quinolines; D011955:Receptors, Drug; D014508:Urea; C476282:cinnoline; D002118:Calcium