Tools to enable the study and translation of supramolecular amphiphiles.

This tutorial review focuses on providing a summary of the key techniques used for the characterisation of supramolecular amphiphiles and their self-assembled aggregates; from the understanding of low-level molecular interactions, to materials analysis, use of data to support computer-aided molecular design and finally, the translation of this class of compounds for real world application, specifically within the clinical setting. We highlight the common methodologies used for the study of traditional amphiphiles and build to provide specific examples that enable the study of specialist supramolecular systems. This includes the use of nuclear magnetic resonance spectroscopy, mass spectrometry, X-ray scattering techniques (small- and wide-angle X-ray scattering and single crystal X-ray diffraction), critical aggregation (or micelle) concentration determination methodologies, machine learning, and various microscopy techniques. Furthermore, this review provides guidance for working with supramolecular amphiphiles in in vitro and in vivo settings, as well as the use of accessible software programs, to facilitate screening and selection of druggable molecules. Each section provides: a methodology overview - information that may be derived from the use of the methodology described; a case study - examples for the application of these methodologies; and a summary section - providing methodology specific benefits, limitations and future applications.

Part 1: N-alkylated glycines as potent α2δ ligands.

A new series of glycine-derived ligands of the α(2)δ subunit of voltage gated calcium channels is described. Several novel compounds (7) based on (6) were prepared that possessed a potency <100 nM in the α(2)δ binding assay.

Part 3: Design and synthesis of proline-derived α2δ ligands.

A potent series of substituted (2S,4S)-benzylproline α(2)δ ligands have been designed from the readily available starting material (2S,4R)-hydroxy-L-proline. The ligands have improved pharmacokinetic profile over the (4S)-phenoxyproline derivatives described previously and have potential for development as oral agents for the treatment of neuropathic pain. Compound 16 has been progressed to clinical development.

Part 2: Design, synthesis and evaluation of hydroxyproline-derived α2δ ligands.

Conformational constraint has been used to design a potent series of α(2)δ ligands derived from the readily available starting material (2S,4R)-hydroxy-l-proline. The ligands have improved physicochemistry and potency compared to their linear counterparts (described in our earlier publication) and the lead compound has been progressed to clinical development.

Synthesis and in vivo evaluation of 3,4-disubstituted gababutins.

A range of 3,4-alkylated five-membered ring derivatives of gabapentin were synthesised. One compound (21) had an excellent level of potency against alpha(2)delta and was profiled in in vivo models of pain and anxiety.

Rapid assessment of a novel series of selective CB(2) agonists using parallel synthesis protocols: A Lipophilic Efficiency (LipE) analysis.

A series of libraries were designed using the 1-(cyclopropylmethyl)-2-alkyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-5-ium templates 2a-b, and Sulfonamide derivatives 11a-n proved to be potent agonists of the CB(2) receptor. Analysis of the Lipophilic Efficiency (LipE) of potent compounds provided new insight for the design of potent, metabolically stable CB2 agonists.

Discovery and Optimization of Selective Nav1.8 Modulator Series That Demonstrate Efficacy in Preclinical Models of Pain.

Voltage-gated sodium channels, in particular Nav1.8, can be targeted for the treatment of neuropathic and inflammatory pain. Herein, we described the optimization of Nav1.8 modulator series to deliver subtype selective, state, and use-dependent chemical matter that is efficacious in preclinical models of neuropathic and inflammatory pain.

Carboxylate bioisosteres of gabapentin.

A series of carboxylate bioisosteres of structures related to gabapentin 1 have been prepared. When the carboxylate was replaced by a tetrazole, this group was recognized by the alpha2-delta protein. Further characterization of alpha2-delta binding compounds 14a and 14b revealed a similar pattern of functional in vitro and in vivo activity to gabapentin 1.