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

Abstract

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.

Bioactive Indanes: Comparative in vitro Metabolism Study of PH46A, a New Potential Anti-inflammatory Agent and Biosynthesis of its Primary Metabolite PH132

“…The detailed NMR spectra and chromatograms are provided in Supplementary Figures S22-S28. 1 H and 13 C NMR data of PH46 were in agreement with the data we previously reported (Figures 9 and 10) [17]. The 1 H NMR spectrum of PH132 ( Figure 11) shared similar spectral pattern as that of PH46.…”

“…In continuation of our work, we more recently designed and synthesized a series of dimeric indane compounds, with two contiguous stereogenic centres, one of which is a quaternary centre. Some of these compounds possess potent anti-inflammatory activity, in particular, a lead chiral molecule PH46A with S,S configurations [14][15][16][17][18], has been identified by our group and was subject to a range of preclinical studies prior to entering a Phase I clinical trial [19]. ADME (Absorption, distribution, metabolism, and excretion) is one of the major elements involved in the drug discovery and development process.…”

The indane diastereoisomers, PH2 and PH5: divergence between their effects in delayed-type hypersensitivity models and a model of colitis

“…We have previously reported that the glutamine salt of the S,S ‐enantiomer of the carboxylic acid derivative of PH5, PH46A has good efficacy in both DSS‐colitis and the IL10 −/− model of spontaneous colitis, models with very different aetiologies . Furthermore, PH46A does not inhibit IL2 release from Jurkat cells (see Fig.…”

2-(Diphenylmethylidene)-2,3-dihydro-1H-inden-1-one

“…For background to the indanone pharmacophore, its use as an organic intermediate and its biological activity, see: Buckle et al (1973); Sheridan et al (1990Sheridan et al ( , 1999aSheridan et al ( ,b, 2008Sheridan et al ( , 2009a; Vacca et al (1994); Schumann et al (2001); Herzog et al (2002); Frankish et al (2004); Frankish & Sheridan (2012); Dinges et al (2006); Kou et al (2012); Ito et al (2004); Jaki et al (1999); Chanda et al (2012); Chen et al (2008); Rukachaisirikul et al (2013); Farrell et al (1996); Borbone et al (2011); Fu & Wang (2008). For bond lengths and angles in related compounds, see: Ali et al (2010aAli et al ( ,b, 2011…”