Optimization of small molecule agonists of the thrombopoietin (Tpo) receptor derived from a benzo[a]carbazole hit scaffold

Protein topology from predicted residue contacts

“…We made the assumption, guided by the NMR structural work reported by Reiter et al.,25 that the compounds all adopt a relatively flat, coplanar conformation. This assumption was also validated by the recent reports of benzo[ a ]carbazole compounds as potent TPO mimetics,28, 29 in which the coplanarity was enforced by cyclisation of the linker region. The molecules were overlaid rigidly, and no allowance was made for the possible rotation of the flexible groups in the central linker region of the molecules.…”

“…Independent academic and pharmaceutical industry research groups have used high‐throughput screening of large libraries of compounds for specific activation of human c‐MPL‐expressing cell lines in the search for small‐molecule TPO mimetics. The screening has identified a diverse range of compounds that act as c‐MPL agonists (or TPO mimetics), such as pyrazol‐4‐ylidenehydrazines,18 salicylaldehyde thiosemicarbazones,19 naphtha[1,2‐ d ]imidazoles,20 benzimidazoles,21 hydrazinothiophenes,22 arylthiazoles,23, 24 benzamides,25–27 benzo[ a ]carbazoles,28, 29 butyzamides,30 and others 31. Subsequent optimisation of the c‐MPL agonist and pharmacokinetic properties has yielded two candidate drugs: Eltrombopag (Promacta/Revolade TM )32, 33 and AKR‐501 34.…”

Palladium-Catalyzed Hydrofunctionalization of Vinyl Phenol Derivatives with Heteroaromatics

“…14 Related tetracyclic indanoindole scaffolds are also found in various biologically active compounds showcasing diverse biological activity. 14a,15 Compound 2a can also be converted to compound 9 in excellent yield via reduction of the corresponding aryl triflate (Figure 2b), which leads to a styrene hydroheteroarylation product and is a common pharmacological framework. 2 Additionally, the treatment of compound 2a with NBS gives the tetracyclic compound 10 in excellent yield (Scheme 3c).…”

Zinc Is Not Required for Activity of TPO Agonists Acting at the c-Mpl Receptor Transmembrane Domain

“…Early work on this class of mimetic (10) identified a molecular feature that was hypothesized to chelate zinc ions and carry them into the c-Mpl transmembrane domain, where they interact with H499 to activate the receptor (see Figure 1). Subsequent work attributed this "zincchelating" role to the 15 or so chemotypes that exhibit TPO agonist activity via this unusual mechanism (19,23). Evidence for this hypothesis was published in a patent by Delorme et al (24).…”