Small molecule analogs of NR58-3.14.3: acylaminoglutarimides and acylaminocaprolactams
Once it became clear that NR58-3.14.3 had exciting properties in vivo, we initiated a search for non-peptide chemical structures which replicated its properties. Such small molecule drugs had the potential for improved pharmacokinetics, lower cost and lower doses when compared to the parental molecules. To this end, we established a productive collaboration with the group of Dr Stuart Warren in the Department of Chemistry, Cambridge University and in 1997, David Fox joined the team as a chemist charged with the task of finding small molecule analogs of NR58-3.14.3.
The first step was to perform a detailed structure:activity relationship (SAR) analysis for the original peptide 3 sequence. Which of the 12 amino acid components were essential for its broad-spectrum chemokine inhibitory activity? We adopted two approaches: deletion analysis, where amino acids from the sequence are deleted in turn until the activity is lost, and substitution analysis, where each amino acid is substituted with a different amino acid in turn. Comfortingly, both approaches yielded similar results - the activity resided in the C-terminal motif WxQ (where W represents the amino acid tryptophan and Q represents the amino acid glutamine and x is any amino acid). The results of this extensive analysis were published in the Journal of Medicinal Chemistry (J Med Chem 45:360).
Armed with this information, David Fox designed a small combinatorial library combining glutamine mimetics with a various simple hydrophobic groups. Fortunately, among the first 16 molecules analysed, we identified one which shared the key properties of NR58-3.14.3. This compound, termed NR58,4, was a simple N-acyl derivative of 3-L-aminoglutarimide. It inhibited leukocyte migration induced by a range of chemokines in the same potency range as NR58-3.14.3 (1-10nM), but did not affect migration induced by other cytokines. NR58,4 was therefore the first non-peptide broad-spectrum chemokine inhibitor (Biochem Pharmacol, 65:1027).
The first steps have already been taken towards improving this initial lead compound (J Med Chem 45:360), but further work needs to be done. The aminoglutarimide ring is subject to enzymatic ring-opening in serum resulting in a short half-life for the active molecule in vivo (J Med Chem 48:867). Removal of the imide carbonyl at position 6 stabilises the molecule, but reduces the biological activity. However, the 7-membered ring lactam analog regains much of the bioactivity. Furthermore, these 7-membered lactam analogs (called acylaminocaprolactams) are also orally bioavailable (J Med Chem 48:867). The best of the published compounds, BN 83253, blocks chemokine-induced migration with an ED50 of 3nM in vtro (comparable with both NR58-3.14.3 and NR58,4) but is also anti-inflammatory in vivo (ED50 at 0.2mg/kg by subcutaneous injection and 2mg/kg via oral dosing). BN 83253 is, therefore, the first stable, cheap to synthesise, potent and orally bioavailable BSCI that we have described. The properties of BSCIs we have published to date were recently reviewed, both for efficacy (Mini Rev Med Chem. 2005;5:825) and toxicology (Mini Rev Med Chem. 2005;5:849)
Unfortunately, BN 83253 is difficult to handle because of its extreme insolubility. This hampers a proper evaluation of its properties in vivo and probably limits the possibility of using it as a human pharmaceutical. Further modifications of this structure, however, have yielded compounds with considerably superior properties. Five compounds, all structurally related to BN83253, have now been extensively evaluated for a range of pharmaceutical properties, including pharmacokinetics, safety pharmacology, preliminary toxicology and pharmacodynamics. Three of the compounds (designated FX125L, FX110L and FX126L) were suitable for development as human pharamceuticals, but FX125L was clearly superior (primarily on the grounds of pharmacokinetics). As a result, FX125L has been designated the lead BSCI for entry into clinical development.
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