Novel, broad-spectrum anticonvulsants containing a sulfamide group: advancement of N-((benzo[b]thien-3-yl)methyl)sulfamide (JNJ-26990990) into human clinical studies

  • J Med Chem. 2009 Dec 10;52(23):7528-36. doi: 10.1021/jm801432r.
Michael H Parker  1 ,  Virginia L Smith-Swintosky ,  David F McComsey ,  Yifang Huang ,  Douglas Brenneman ,  Brian Klein ,  Ewa Malatynska ,  H Steve White ,  Michael E Milewski ,  Mark Herb ,  Michael F A Finley ,  Yi Liu ,  Mary Lou Lubin ,  Ning Qin ,  Robert Iannucci ,  Laurent Leclercq ,  Filip Cuyckens ,  Allen B Reitz ,  Bruce E Maryanoff
Affiliations
  • 1. Research and Early Development, Johnson & Johnson Pharmaceutical Research & Development, Spring House, Pennsylvania 19477-0776, USA.
PMID: 19388676 DOI: 10.1021/jm801432r
Abstract

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.

Products