Pyrazolopyridazine alpha-2-delta-1 ligands for the treatment of neuropathic pain

doi:10.1016/j.bmcl.2010.05.026

Bioorganic & Medicinal Chemistry Letters

Volume 20, Issue 15, 1 August 2010, Pages 4683-4688

https://doi.org/10.1016/j.bmcl.2010.05.026 Get rights and content

Abstract

Optimization of the novel alpha-2-delta-1 ligand 4 provided compounds 37 and 38 which have improved DMPK profiles, good in vivo analgesic activity and in vitro selectivity over alpha-2-delta-2. An in-house P-gp prediction programme and the MetaSite® software package were used to help solve the specific problems of high P-gp efflux and high in vivo clearance.

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Citation Excerpt :
Abraham’s β parameter was also reported as one of the key descriptors for the probabilistic model along with volume and indicator variables for acidic or basic nature of the compounds. In an interesting case study of voltage-gated calcium channel inhibitors for the potential treatment of neuropathic pain, an amino-substituted pyrazolopyridazine 1 (Table 1) was identified as the key starting point; however, it suffered from high clearance in rats.32 In an attempt to reduce the clearance, the authors designed and synthesized compounds with lower hydrophobicity through the introduction of polar functional groups, exemplified by 2–4 (Table 1).
The requirement to cross a biological membrane can be a complex process especially if multidrug transporters such as P-gp must be considered. Drug partitioning into the lipid membrane and efflux by P-gp are tightly coupled processes wherein H-bonding interactions play a key role. All H-bond donors and acceptors are not equal in terms of the strength of the H-bonds that they form, hence it is important to consider their relative strength. Using various examples from literature, we illustrate the benefits of considering the relative strengths of individual H-bonds and introducing intramolecular H-bonds to increase membrane permeability and/or decrease P-gp efflux.
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Pyrazolopyridazine alpha-2-delta-1 ligands for the treatment of neuropathic pain

Abstract

Graphical abstract

Neuropharmacology

Neurosci. Lett.

Pain

Curr. Opin. Pharmacol.

J. Pharmacol. Sci.

Trends Pharmacol. Sci.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Brain Res.

Neuroscience

J. Pharmacol. Exp. Ther.

J. Med. Chem.

Receptors Channels

BMC Pharmacol.