Synthesis and pharmacological evaluation of N,N'-diarylguanidines as potent sodium channel blockers and anticonvulsant agents.
Synthesis and structure-activity relationships (SAR) are described for a series of N,N'-diarylguanidines related to N-acenaphth-5-yl-N'-(4-methoxynaphth-1-yl)guanidine (3) as anticonvulsants through blockade of sodium channels. SAR studies on compound 3 led to several simpler diphenylguanidines with improved in vitro and in vivo activity. Compounds were screened for blockade of sodium channels in a veratridine-induced [14C]guanidinium influx assay (type IIA sodium channels) and for anticonvulsant activity in the audiogenic DBA/2 mouse model. Results indicated that N, N'-diphenylguanidines substituted with flexible and moderate size lipophilic groups were preferred over aryl and/or hydrophilic groups for biological activity. Among the compounds studied, n-butyl- and/or n-butoxy-containing guanidines showed superior biological activity. A possible relationship between in vitro and in vivo activity of this compound series and their measured/calculated lipophilicities was investigated. Compounds of this series showed only weak NMDA ion channel-blocking activity indicating that the anticonvulsant activity of these compounds is unlikely to be mediated by NMDA ion channels but, more likely, by acting at voltage-gated sodium channels.
Cambridge NeuroScience, Inc., Cambridge, Massachusetts 02139, USA. lreddy@pharmeco.com
N L
NL
Reddy
W
W
Fan
S S
SS
Magar
M E
ME
Perlman
E
E
Yost
L
L
Zhang
D
D
Berlove
J B
JB
Fischer
K
K
Burke-Howie
T
T
Wolcott
G J
GJ
Durant
D000161:Acoustic Stimulation; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D015195:Drug Design; D019791:Guanidine / Q000378:metabolism; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008811:Mice, Inbred DBA; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D019782:Riluzole / Q000737:chemistry / Q000494:pharmacology; D012640:Seizures / Q000517:prevention & control*; D026941:Sodium Channel Blockers; D013329:Structure-Activity Relationship; D014701:Veratridine / Q000494:pharmacology
D000927:Anticonvulsants; D006146:Guanidines; D010879:Piperazines; D011743:Pyrimidines; D026941:Sodium Channel Blockers; D014701:Veratridine; D019782:Riluzole; D019791:Guanidine; C081980:sipatrigine