Discovery of SB-705498: a potent, selective and orally bioavailable TRPV1 antagonist suitable for clinical development.
Small molecule antagonists of the vanilloid receptor TRPV1 (also known as VR1) are disclosed. Pyrrolidinyl ureas such as 8 and 15 (SB-705498) emerged as lead compounds following optimisation of the previously described urea SB-452533. Pharmacological studies using electrophysiological and FLIPR-Ca2+-based assays showed that compounds such as 8 and 15 were potent antagonists versus the multiple chemical and physical modes of TRPV1 activation (namely capsaicin, acid and noxious heat). Furthermore, 15 possessed suitable developability properties to enable progression of this compound into in vivo studies and subsequently clinical development.
Rami
Harshad K
HK
Neurology and GI CEDD, New Frontiers Science Park, GlaxoSmithKline, Third Avenue, Harlow, Essex CM19 5AW, UK. Harshad.Rami@gsk.com
Thompson
Mervyn
M
Stemp
Geoffrey
G
Fell
Steve
S
Jerman
Jeffrey C
JC
Stevens
Alexander J
AJ
Smart
Darren
D
Sargent
Becky
B
Sanderson
Dominic
D
Randall
Andrew D
AD
Gunthorpe
Martin J
MJ
Davis
John B
JB
D000284:Administration, Oral; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D002460:Cell Line; D015195:Drug Design; D006168:Guinea Pigs; D006801:Humans; D015394:Molecular Structure; D011759:Pyrrolidines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D011759:Pyrrolidines; C512301:SB 705498; D050916:TRPV Cation Channels; D014508:Urea; C032519:pyrrolidine; D002211:Capsaicin