Discovery and synthesis of a novel and selective drug-like P2X(1) antagonist.
Although there is extensive literature to indicate that many different types of P2 purinoceptors are present in the lower urinary tract, the physiological role of these receptors in micturition is still uncertain. In part, this uncertainty has been caused by a lack of P2 subtype selective ligands. In this paper we report the discovery, gram scale synthesis, and binding results for 1, the first potent, drug-like, selective P2X(1) receptor antagonist described. Compound 1 was shown to be more than 30-fold selective over other purinergic receptor subtypes.
Jaime-Figueroa
S
S
Roche Palo Alto, 3431 Hillview Ave., Palo Alto, CA 94304, USA. saul.jaime@roche.com
Greenhouse
R
R
Padilla
F
F
Dillon
M P
MP
Gever
J R
JR
Ford
A P D W
AP
D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000032:analysis; D002460:Cell Line; D002470:Cell Survival; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D058919:Purinergic P2 Receptor Antagonists; D058469:Receptors, Purinergic P2X; D013329:Structure-Activity Relationship; D014162:Transfection
D000577:Amides; D008024:Ligands; D058919:Purinergic P2 Receptor Antagonists; D058469:Receptors, Purinergic P2X; D002118:Calcium