Identification and SAR of selective inducible nitric oxide synthase (iNOS) dimerization inhibitors

Timothy C Gahman; Mark R Herbert; Henk Lang; Angie Thayer; Kent T Symons; Phan Manh Nguyen; Mark E Massari; Sara Dozier; Yan Zhang; Marciano Sablad; Tadimeti S Rao; Stewart A Noble; Andrew K Shiau; Christian A Hassig

doi:10.1016/j.bmcl.2011.08.112

Identification and SAR of selective inducible nitric oxide synthase (iNOS) dimerization inhibitors

Bioorg Med Chem Lett. 2011 Nov 15;21(22):6888-94. doi: 10.1016/j.bmcl.2011.08.112. Epub 2011 Sep 8.

Authors

Timothy C Gahman¹, Mark R Herbert, Henk Lang, Angie Thayer, Kent T Symons, Phan Manh Nguyen, Mark E Massari, Sara Dozier, Yan Zhang, Marciano Sablad, Tadimeti S Rao, Stewart A Noble, Andrew K Shiau, Christian A Hassig

Affiliation

¹ Department of Medicinal Chemistry, Kalypsys Inc., 10420 Wateridge Circle, San Diego, CA 92121, USA. tgahman@gmail.com

PMID: 21986586
DOI: 10.1016/j.bmcl.2011.08.112

Abstract

We have identified and synthesized a series of imidazole containing dimerization inhibitors of inducible nitric oxide synthase (iNOS). The necessity of key imidazole and piperonyl functionality was demonstrated and SAR studies led to the identification of compound 35, which showed a dose dependant inhibition in multiple pain models, including tactile allodynia induced by spinal nerve ligation (Chung model).

MeSH terms

Animals
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology
Enzyme Inhibitors / therapeutic use*
Female
Humans
Hyperalgesia / drug therapy*
Imidazoles / chemistry*
Imidazoles / pharmacology
Imidazoles / therapeutic use*
Nitric Oxide Synthase Type II / antagonists & inhibitors*
Nitric Oxide Synthase Type II / metabolism
Pain / drug therapy*
Protein Multimerization / drug effects*
Rats
Rats, Inbred Lew

Substances

Enzyme Inhibitors
Imidazoles
Nitric Oxide Synthase Type II