Synthesis and biological evaluation of the 1-arylpyrazole class of σ(1) receptor antagonists: identification of 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862).
The synthesis and pharmacological activity of a new series of 1-arylpyrazoles as potent σ(1) receptor (σ(1)R) antagonists are reported. The new compounds were evaluated in vitro in human σ(1)R and guinea pig σ(2) receptor (σ(2)R) binding assays. The nature of the pyrazole substituents was crucial for activity, and a basic amine was shown to be necessary, in accordance with known receptor pharmacophores. A wide variety of amines and spacer lengths between the amino and pyrazole groups were tolerated, but only the ethylenoxy spacer and small cyclic amines provided compounds with sufficient selectivity for σ(1)R vs σ(2)R. The most selective compounds were further profiled, and compound 28, 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862), which showed high activity in the mouse capsaicin model of neurogenic pain, emerged as the most interesting candidate. In addition, compound 28 exerted dose-dependent antinociceptive effects in several neuropathic pain models. This, together with its good physicochemical, safety, and ADME properties, led compound 28 to be selected as clinical candidate.
Drug Discovery and Preclinical Development, Esteve, Av. Mare de Déu de Montserrat, 221, 08041, Barcelona, Spain. jldiaz@esteve.es
José Luis
JL
Díaz
Rosa
R
Cuberes
Joana
J
Berrocal
Montserrat
M
Contijoch
Ute
U
Christmann
Ariadna
A
Fernández
Adriana
A
Port
Jörg
J
Holenz
Helmut
H
Buschmann
Christian
C
Laggner
Maria Teresa
MT
Serafini
Javier
J
Burgueño
Daniel
D
Zamanillo
Manuel
M
Merlos
José Miguel
JM
Vela
Carmen
C
Almansa
D000818:Animals; D001921:Brain / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009437:Neuralgia / Q000188:drug therapy / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D020426:Sciatic Neuropathy / Q000188:drug therapy / Q000503:physiopathology; D013329:Structure-Activity Relationship; D000097605:Sigma-1 Receptor
D009025:Morpholines; D011720:Pyrazoles; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C576663:4-(2-((5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl)oxy)ethyl)morpholine