Details

Autor(en) / Beteiligte

• DiMauro, Erin F
• Altmann, Stephen
• Berry, Loren M
• Bregman, Howard
• Chakka, Nagasree
• Chu-Moyer, Margaret
• Bojic, Elma Feric
• Foti, Robert S
• Fremeau, Robert
• Gao, Hua
• Gunaydin, Hakan
• Guzman-Perez, Angel
• Hall, Brian E
• Huang, Hongbing
• Jarosh, Michael
• Kornecook, Thomas
• Lee, Josie
• Ligutti, Joseph
• Liu, Dong
• Moyer, Bryan D
• Ortuno, Daniel
• Rose, Paul E
• Schenkel, Laurie B
• Taborn, Kristin
• Wang, Jean
• Wang, Yan
• Yu, Violeta
• Weiss, Matthew M

Titel

Application of a Parallel Synthetic Strategy in the Discovery of Biaryl Acyl Sulfonamides as Efficient and Selective NaV1.7 Inhibitors

Ist Teil von

• Journal of medicinal chemistry, 2016-09, Vol.59 (17), p.7818-7839

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• The majority of potent and selective hNaV1.7 inhibitors possess common pharmacophoric features that include a heteroaryl sulfonamide headgroup and a lipophilic aromatic tail group. Recently, reports of similar aromatic tail groups in combination with an acyl sulfonamide headgroup have emerged, with the acyl sulfonamide bestowing levels of selectivity over hNaV1.5 comparable to the heteroaryl sulfonamide. Beginning with commercially available carboxylic acids that met selected pharmacophoric requirements in the lipophilic tail, a parallel synthetic approach was applied to rapidly generate the derived acyl sulfonamides. A biaryl acyl sulfonamide hit from this library was elaborated, optimizing for potency and selectivity with attention to physicochemical properties. The resulting novel leads are potent, ligand and lipophilic efficient, and selective over hNaV1.5. Representative lead 36 demonstrates selectivity over other human NaV isoforms and good pharmacokinetics in rodents. The biaryl acyl sulfonamides reported herein may also offer ADME advantages over known heteroaryl sulfonamide inhibitors.