6-(methylamino)hexane-1,2,3,4,5-pentanol 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1'H-[2,2-biinden]-2-yl)methyl)benzoate (PH46A): a novel small molecule with efficacy in murine models of colitis.
The indane skeleton is found naturally and in several therapeutic molecules in medicinal chemistry. During our work on the anti-inflammatory activity of naturally occurring and synthetic indanes, we have synthesized a novel indane scaffold that has been optimized for both anti-inflammatory activity and bioavailability. We have evaluated our lead molecule, PH46A, in in vivo models of inflammatory bowel disease (IBD), an area of considerable unmet clinical need; current therapies are often unable to control the course of the disease. The compound significantly reduced histological damage and serum amyloid A (SAA) levels in IL-10(-/-) colitis mice, was efficacious in the 5% dextran sulfate sodium (DSS) colitis model, and compared favorably with prednisolone in this model and supports its potential use to treat acute exacerbations of the disease. Further, the graded response to the compound may also lend itself to be used at a lower dose to maintain periods of remission.
Trinity College Dublin, Drug Discovery Group, School of Pharmacy and Pharmaceutical Sciences, College Green, Dublin 2, Ireland. nfrnkish@tcd.ie
Neil
N
Frankish
Helen
H
Sheridan
D000208:Acute Disease; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002908:Chronic Disease; D003092:Colitis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006471:Gastrointestinal Hemorrhage / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D007189:Indans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016753:Interleukin-10 / Q000235:genetics; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D000685:Serum Amyloid A Protein / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015431:Weight Loss
C575286:4-((1-hydroxy-2,3-dihydro-1H,1'H-(2,2-biinden)-2-yl)methyl)benzoic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007189:Indans; D000685:Serum Amyloid A Protein; D016753:Interleukin-10