ABSTRACT
Broad-spectrum anticonvulsants are of considerable interest as antiepileptic drugs, especially because of their potential for treating refractory patients. Such "neurostabilizers" have also been used to treat other neurological disorders, including migraine, bipolar disorder, and neuropathic pain. We synthesized a series of sulfamide derivatives (4-9, 10a-i, 11a, 11b, 12) and evaluated their anticonvulsant activity. Thus, we identified promising sulfamide 4 (JNJ-26489112) and explored its pharmacological properties. Compound 4 exhibited excellent anticonvulsant activity in rodents against audiogenic, electrically induced, and chemically induced seizures. Mechanistically, 4 inhibited voltage-gated Na(+) channels and N-type Ca(2+) channels and was effective as a K(+) channel opener. The anticonvulsant profile of 4 suggests that it may be useful for treating multiple forms of epilepsy (generalized tonic-clonic, complex partial, absence seizures), including refractory (or pharmacoresistant) epilepsy, at dose levels that confer a good safety margin. On the basis of its pharmacology and other favorable characteristics, 4 was advanced into human clinical studies.
Subject(s)
Amides/chemistry , Amides/pharmacology , Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Dioxanes/chemistry , Dioxanes/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology , Absorption , Amides/pharmacokinetics , Amides/therapeutic use , Animals , Anticonvulsants/pharmacokinetics , Anticonvulsants/therapeutic use , Dioxanes/pharmacokinetics , Dioxanes/therapeutic use , Dogs , Drug Evaluation, Preclinical , Drug Resistance , Epilepsy/drug therapy , Female , Humans , Male , Mice , Rats , Sulfonamides/pharmacokinetics , Sulfonamides/therapeutic useABSTRACT
In seeking broad-spectrum anticonvulsants to treat epilepsy and other neurological disorders, we synthesized and tested a group of sulfamide derivatives (4a-k, 5), which led to the clinical development of 4a (JNJ-26990990). This compound exhibited excellent anticonvulsant activity in rodents against audiogenic, electrically induced, and chemically induced seizures, with very weak inhibition of human carbonic anhydrase-II (IC(50) = 110 microM). The pharmacological profile for 4a supports its potential in the treatment of multiple forms of epilepsy, including pharmacoresistant variants. Mechanistically, 4a inhibited voltage-gated Na(+) channels and N-type Ca(2+) channels but was not effective as a K(+) channel opener. The pharmacokinetics and metabolic properties of 4a are discussed.
Subject(s)
Amides/chemistry , Amides/pharmacology , Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology , Thiophenes/chemistry , Thiophenes/pharmacology , Amides/metabolism , Amides/pharmacokinetics , Animals , Anticonvulsants/metabolism , Anticonvulsants/pharmacokinetics , Carbonic Anhydrase II/antagonists & inhibitors , Cell Line , Clinical Trials as Topic , Drug Evaluation, Preclinical , Female , Humans , Male , Mice , Rats , Sulfonamides/metabolism , Sulfonamides/pharmacokinetics , Thiophenes/metabolism , Thiophenes/pharmacokineticsABSTRACT
General screening for inhibitors of microvessel growth in vitro in the rat aortic ring assay led to the discovery of a novel series of thiadiazole pyridazine compounds with potential anti-angiogenic activity. Chemical optimization produced orally active compounds with potent in vitro and in vivo anti-angiogenesis and anti-tumor activities.
