Fiona Chan

Substituted 4-phenyl-2-aminoimidazoles and 4-phenyl-4,5-dihydro-2-aminoimidazoles as voltage-gated sodium channel modulators.

Voltage-gated sodium channels play an integral part in neurotransmission and their dysfunction is frequently a cause of various neurological disorders. On the basis of the structure of marine alkaloid clathrodin, twenty eight new analogs were designed, synthesized and tested for their ability to block human NaV1.3, NaV1.4 and NaV1.7 channels, as well as for their selectivity against human cardiac isoform NaV1.5, using automated patch clamp electrophysiological assay. Several compounds exhibited promising activities on different NaV channel isoforms in the medium micromolar range and some of the compounds showed also moderate isoform selectivities. The most promising results were obtained for the NaV1.3 channel, for which four compounds were found to possess IC₅₀ values lower than 15 μM. All of the active compounds bind to the open-inactivated states of the channels and therefore act as state-dependent modulators. The obtained results validate the approach of using natural products driven chemistry for drug discovery starting points and represent a good foundation for future design of selective NaV modulators.

Novel state-dependent voltage-gated sodium channel modulators, based on marine alkaloids from Agelas sponges.

Clathrodin, alkaloid isolated from Agelas sponges, was reported in 1995 as a voltage-gated sodium channel modulator. Here we describe the design and synthesis of conformationally restricted clathrodin analogues incorporating the 4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine moiety and evaluation of their modulatory activities on human voltage-gated sodium channel isoforms Na(v)1.3, Na(v)1.4 and Na(v)1.7, as well as their selectivity against cardiac isoform Na(v)1.5. Compounds were shown to act as state-dependent modulators of Na(v)1.3, Na(v)1.4 and Na(v)1.7 with IC₅₀ values in the lower micromolar range for the open-inactivated state of the channels. Preliminary structure-activity relationship studies have revealed the importance of hydrophobic interactions for binding to all three tested isoforms. Compound 4e with IC₅₀ value of 8 μM against Na(v)1.4 represents a novel selective state-dependent Na(v)1.4 channel modulator.

Ligand- and structure-based virtual screening for clathrodin-derived human voltage-gated sodium channel modulators.

Voltage-gated sodium channels (VGSC) are attractive targets for drug discovery because of the broad therapeutic potential of their modulators. On the basis of the structure of marine alkaloid clathrodin, we have recently discovered novel subtype-selective VGSC modulators I and II that were used as starting points for two different ligand-based virtual screening approaches for discovery of novel VGSC modulators. Similarity searching in the ZINC database of drug-like compounds based on compound I resulted in five state-dependent Na(v)1.3 and Na(v)1.7 modulators with improved activity compared to I (IC₅₀ < 20 μM). Compounds 2 and 16 that blocked sodium permeation in Na(v)1.7 with IC₅₀ values of 7 and 9 μM, respectively, are among the most potent clathrodin analogs discovered so far. In the case of compound II, 3D similarity searching in the same database was followed by docking of an enriched compound library into our human Na(v)1.4 open-pore homology model. Although some of the selected compounds, e.g., 31 and 32 displayed 21% and 22% inactivated state I(peak) block of Na(v)1.4 at 10 μM, respectively, none showed better Na(v)1.4 modulatory activity than compound II. Taken together, virtual screening yielded compounds 2 and 16, which represent novel scaffolds for the discovery of human Na(v)1.7 modulators.

Naphthol derivatives as TRPV1 inhibitors for the treatment of urinary incontinence.

We have identified naphthol derivatives as inhibitors of the vanilloid receptor TRPV1 by high throughput screening. The initial lead showed high clearance in rats and has been optimized by enhancing the acidity of the phenol group. Compound 6b has reduced clearance, improved potency and is active in rat cystometry models of urinary incontinence after intravenous administration.

Tetrahydro-naphthols as orally available TRPV1 inhibitors.

Starting from a naphthol-based lead series with low oral bioavailability, we have identified potent TRPV1 antagonists with oral bioavailability in rats. These compounds emerged from SAR studies aimed at replacing the leads phenol structure whilst maintaining potency. Compound rac-6a is an orally available TRPV1 antagonist with single-digit nanomolar activity. The enantiomers show a low eudismic ratio at the receptor level.