Synthesis and structure-activity relationships of 6-heterocyclic-substituted purines as inactivation modifiers of cardiac sodium channels.
Purine-based analogs of SDZ 211-500 (5) were prepared and evaluated as inactivation modifiers of guinea pig or human cardiac sodium (Na) channels expressed in Xenopus oocytes. Substances which remove or slow the Na channel inactivation process in cardiac tissue are anticipated to prolong the effective refractory period and increase inotropy and thus have potential utility as antiarrhythmic agents. Heterocyclic substitution at the 6-position of the purine ring resulted in compounds with increased Na activity and potency, with 5-membered heterocycles being optimal. Only minor modifications to the benzhydrylpiperazine side chain were tolerated. Selected compounds which delayed the inactivation of Na channels were found to increase refractoriness and contractility in a rabbit Langendorff heart model, consistent with the cellular mechanism. Activity in both the oocyte and rabbit heart assays was specific to the S enantiomers. Preliminary in vivo activity has been demonstrated following intravenous infusion. The most promising compound on the basis of in vitro data is the formylpyrrole (S)-74, which is 25-fold more potent than DPI 201-106 (1) in the human heart Na channel assay.
Estep
K G
KG
Department of Medicinal Chemistry, Sterling Winthrop Pharmaceuticals Research Division, Sterling Winthrop Inc., Collegeville, Pennsylvania 19426-0900, USA.
Josef
K A
KA
Bacon
E R
ER
Carabateas
P M
PM
Rumney
S
S
Pilling
G M
GM
Krafte
D S
DS
Volberg
W A
WA
Dillon
K
K
Dugrenier
N
N
D000818:Animals; D002415:Cats; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000737:chemistry*; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D026941:Sodium Channel Blockers; D013329:Structure-Activity Relationship; D014981:Xenopus
D006571:Heterocyclic Compounds; D011687:Purines; D026941:Sodium Channel Blockers