ABSTRACT
The voltage-gated sodium channel Nav1.7 is a genetically validated target for the treatment of pain with gain-of-function mutations in man eliciting a variety of painful disorders and loss-of-function mutations affording insensitivity to pain. Unfortunately, drugs thought to garner efficacy via Nav1 inhibition have undesirable side effect profiles due to their lack of selectivity over channel isoforms. Herein we report the discovery of a novel series of orally bioavailable arylsulfonamide Nav1.7 inhibitors with high levels of selectivity over Nav1.5, the Nav isoform responsible for cardiovascular side effects, through judicious use of parallel medicinal chemistry and physicochemical property optimization. This effort produced inhibitors such as compound 5 with excellent potency, selectivity, behavioral efficacy in a rodent pain model, and efficacy in a mouse itch model suggestive of target modulation.
Subject(s)
Sulfonamides/chemistry , Voltage-Gated Sodium Channel Blockers/chemistry , Administration, Oral , Animals , Disease Models, Animal , Drug Evaluation, Preclinical , Half-Life , Inhibitory Concentration 50 , Mice , NAV1.7 Voltage-Gated Sodium Channel/chemistry , NAV1.7 Voltage-Gated Sodium Channel/metabolism , Nitrogen/chemistry , Pain/drug therapy , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Rats , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Sulfonamides/therapeutic use , Voltage-Gated Sodium Channel Blockers/pharmacokinetics , Voltage-Gated Sodium Channel Blockers/therapeutic useABSTRACT
We have identified several series of small molecule inhibitors of TrkA with unique binding modes. The starting leads were chosen to maximize the structural and binding mode diversity derived from a high throughput screen of our internal compound collection. These leads were optimized for potency and selectivity employing a structure based drug design approach adhering to the principles of ligand efficiency to maximize binding affinity without overly relying on lipophilic interactions. This endeavor resulted in the identification of several small molecule pan-Trk inhibitor series that exhibit high selectivity for TrkA/B/C versus a diverse panel of kinases. We have also demonstrated efficacy in both inflammatory and neuropathic pain models upon oral dosing. Herein we describe the identification process, hit-to-lead progression, and binding profiles of these selective pan-Trk kinase inhibitors.
Subject(s)
Chronic Pain/drug therapy , Protein Kinase Inhibitors/chemistry , Receptor, trkA/antagonists & inhibitors , Animals , Drug Evaluation, Preclinical , Humans , Indoles/chemistry , Indoles/pharmacokinetics , Ligands , Models, Molecular , Protein Kinase Inhibitors/pharmacokinetics , Pyrimidines/chemistry , Pyrimidines/pharmacokinetics , Rats , Small Molecule Libraries/therapeutic use , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/pharmacokinetics , Urea/analogs & derivatives , Urea/chemistry , Urea/pharmacokineticsABSTRACT
A series of HIV-1 protease inhibitors containing an epsilon substituted lysinol backbone was synthesized. Two novel synthetic routes using N-boc-L-glutamic acid alpha-benzyl ester and 2,6-diaminopimelic acid were developed. Incorporation of this epsilon substituent enabled access to the S2 pocket of the enzyme, affording high potency inhibitors. Modeling studies and synthetic efforts suggest the potency increase is due to both conformational bias and van der Waals interactions with the S2 pocket.
Subject(s)
HIV Protease Inhibitors/pharmacology , Lysine/analogs & derivatives , HIV Protease Inhibitors/chemistry , Models, Molecular , Structure-Activity RelationshipABSTRACT
We have developed a novel series of heteroaromatic BACE-1 inhibitors. These inhibitors interact with the enzyme in a unique fashion that allows for potent binding in a non-traditional paradigm. In addition to the elucidation of their binding profile, we have discovered a pH dependent effect on the binding affinity as a result of the intrinsic pK(a) of these inhibitors and the pH of the BACE-1 enzyme binding assay.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Heterocyclic Compounds/chemistry , Amyloid Precursor Protein Secretases/metabolism , Crystallography, X-Ray , Drug Design , Enzyme Inhibitors/pharmacology , Heterocyclic Compounds/pharmacology , Hydrogen-Ion Concentration , Protein Binding , Structure-Activity RelationshipABSTRACT
Extracellular deposits of aggregated amyloid-beta (Abeta) peptides are a hallmark of Alzheimer disease; thus, inhibition of Abeta production and/or aggregation is an appealing strategy to thwart the onset and progression of this disease. The release of Abeta requires processing of the amyloid precursor protein (APP) by both beta- and gamma-secretase. Using an assay that incorporates full-length recombinant APP as a substrate for beta-secretase (BACE), we have identified a series of compounds that inhibit APP processing, but do not affect the cleavage of peptide substrates by BACE1. These molecules also inhibit the processing of APP and Abeta by BACE2 and selectively inhibit the production of Abeta(42) species by gamma-secretase in assays using CTF99. The compounds bind directly to APP, likely within the Abeta domain, and therefore, unlike previously described inhibitors of the secretase enzymes, their mechanism of action is mediated through APP. These studies demonstrate that APP binding agents can affect its processing through multiple pathways, providing proof of concept for novel strategies aimed at selectively modulating Abeta production.
