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C286, (4-(5-(4,7-dimethylbenzofuran-2-yl)-1,2,4-oxadiazol-3-yl) benzoic acid) is a potent orally bioavailable retinoic acid receptor beta (RARβ) agonist (EC50 = 1.9nM) with good selectivity over the RARα, and RARγ receptors. . This molecule increases neurite outgrowth in vitro and induces sensory axon regrowth in vivo in a rodent model of avulsion and crush injury, and is being evaluated for the treatment of nerve injury.

Discovery and Design
Replacing the amide linkage in the novel selective RARα agonist 1 with a series of 5-membered heterocyclic rings, gave compounds which were selective as RARβ agonists. The best was the oxadiazole 2, a highly potent RARβ agonist and that had 12- and 19-fold selectivity as an agonist over RARα and RARγ respectively. Lead optimisation produced the highly potent and selective RARβ agonist 4-(5-(4,7-dimethylbenzofuran-2-yl)-1,2,4-oxadiazol-3-yl) benzoic acid C286.

Mechanism of action
It has been shown that RARβ signalling is required for retinoid mediated neurite outgrowth of neurons. In contrast, signalling by RARα, RARγ or the retinoid X receptor (RXR) has no effect on this action. The RARβ agonist C286 can activate the RARβ receptor which initiates axonal outgrowth in models of nerve injury and leads to functional recovery.

Pharmacology
C286 has been demonstrated to increase neurite outgrowth in vitro in monolayers of cultured cerebellar neurons where it increased neurite length in a dose dependant manner. C286 orally induces sensory axon regrowth in vivo in a rodent model of crush and avulsion injury. In addition C286 has shown a novel function for RARβ in remyelination after peripheral nervous system / central nervous system injury, and also demonstrates efficacy in a pre-clinical neuropathic pain model restoring multiple pathways via DNA repair mechanisms.

Pharmacokinetics
C286 has human and mouse plasma protein binding of 98% and 95% respectively and has excellent physico-chemical properties. It is sufficiently water soluble (> 100 μM as the sodium salt) and showed good permeability. The efflux ratios obtained from bi-directional permeability tests was close to unity indicating that C286 is likely not a P-glycoprotein substrate. It has no significant inhibition IC50 > 25 μM against five cytochrome P450 enzymes (1A2, 2C9, 2C19, 2D6, 3A4), and shows very high stability in human microsomes, It was found to possess a good oral bioavailability in both rat (80%) and dog (45%). with a low rate of blood clearance and a moderate half-life in both species. It was also found to penetrate the CNS, with nearly equivalent amounts detected in brain tissue when compared to plasma, 8 hours after dosing orally to rats. C286 was also shown to be negative in the cytotoxicity and genotoxicity in-vitro screens.

Synthesis
Addition of hydroxylamine to methyl para-cyano-benzoate 3 gave the amidoxime 4 which was coupled with the acid 5 to give after hydrolysis the 4-(5-(4,7-dimethylbenzofuran-2-yl)-1,2,4-oxadiazol-3-yl) benzoic acid C286.

History
Although many synthetic selective RARα, RARβ, and RARγ agonists have been designed and prepared, these have generally been highly lipophilic acids without good drug-like properties and with low oral bioavailability. Recently this has been changing and drug design approaches to highly potent and selective RARα and RARβ agonists with low lipophilicity that are orally bioavailable and less toxic have been developed. A key element of this success has been the incorporation of heterocyclic linkers culminating in the discovery of the selective RAR beta agonist C286 showing high solubility and good oral pharmacokinetics. C286 is currently in Phase I clinical trials (ISRCTN12424734).