Synthesis and biological evaluation of biaryl alkyl ethers as inhibitors of IDO1.

Starting from the dialkylaniline indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor lead 3 (IDO1 HeLa IC = 7.0 nM), an iterative process of synthesis and screening led to cyclized analog 21 (IDO1 HeLa IC = 3.6 nM) which maintained the high potency of 3 while addressing issues of lipophilicity, cytochrome P450 (CYP) inhibition, hERG (human potassium ion channel Kv11.

Discovery of BMS-986339, a Pharmacologically Differentiated Farnesoid X Receptor Agonist for the Treatment of Nonalcoholic Steatohepatitis.

While several farnesoid X receptor (FXR) agonists under clinical investigation for the treatment of nonalcoholic steatohepatitis (NASH) have shown beneficial effects, adverse effects such as pruritus and elevation of plasma lipids have limited their clinical efficacy and approvability. Herein, we report the discovery and preclinical evaluation of compound (BMS-986339), a nonbile acid FXR agonist with a pharmacologically distinct profile relative to our previously reported agonist BMS-986318. Compound exhibited potent in vitro and in vivo activation of FXR, albeit with a context-dependent profile that resulted in tissue-selective effects in vivo.

Bicyclic Heterocyclic Replacement of an Aryl Amide Leading to Potent and Kinase-Selective Adaptor Protein 2-Associated Kinase 1 Inhibitors.

Adaptor protein 2-associated kinase 1 (AAK1) is a serine/threonine kinase that was identified as a therapeutic target for the potential treatment of neuropathic pain. Inhibition of AAK1 in the central nervous system, particularly within the spinal cord, was found to be the relevant site for achieving an antinociceptive effect. We previously reported that compound is a brain-penetrant, AAK1 inhibitor that showed efficacy in animal models for neuropathic pain.

[H]BMT-046091 a potent and selective radioligand to determine AAK1 distribution and target engagement.

Adaptor-associated kinase 1 (AAK1), a member of the Ark1/Prk1 family of serine/threonine kinases, plays a role in modulating clatherin coated endocytosis of specific surface receptors. We have demonstrated that AAK1 inhibitors are efficacious in rodent models of neuropathic pain (Kostich et al., 2016).

Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain.

To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL).

3-Pyridinols and 5-pyrimidinols: Tailor-made for use in synergistic radical-trapping co-antioxidant systems.

The incorporation of nitrogen atoms into the aromatic ring of phenolic compounds has enabled the development of some of the most potent radical-trapping antioxidants ever reported. These compounds, 3-pyridinols and 5-pyrimidinols, have stronger O-H bonds than equivalently substituted phenols, but possess similar reactivities toward autoxidation chain-carrying peroxyl radicals. These attributes suggest that 3-pyridinols and 5-pyrimidinols will be particularly effectiveco-antioxidants when used in combination with more common, but less reactive, phenolic antioxidants such as 2,6-di-tert-butyl-4-methylphenol (BHT), which we demonstrate herein.

Pyridine and pyrimidine analogs of acetaminophen as inhibitors of lipid peroxidation and cyclooxygenase and lipoxygenase catalysis.

Herein we report an investigation of the efficacy of pyridine and pyrimidine analogs of acetaminophen (ApAP) as peroxyl radical-trapping antioxidants and inhibitors of enzyme-catalyzed lipid peroxidation by cyclooxygenases (COX) and lipoxygenases (LOX). In inhibited autoxidations we find that ApAP, the common analgesic and antipyretic agent, is a very good antioxidant with a rate constant for reaction with peroxyl radicals (k(inh) = 5 x 10(5) M(-1) s(-1)) that is higher than many widely-used phenolic antioxidants, such as the ubiquitous butylated hydroxytoluene (BHT). This reactivity is reduced substantially upon incorporation of nitrogen into the phenolic ring, owing to an increase in the O-H bond dissociation enthalpy of pyridinols and pyrimidinols with respect to phenols.

Tyrosine analogues for probing proton-coupled electron transfer processes in peptides and proteins.

A series of amino acids analogous to tyrosine, but differing in the physicochemical properties of the aryl alcohol side chain, have been prepared and characterized. These compounds are expected to be useful in understanding the relationships between structure, thermodynamics, and kinetics in long-range proton-coupled electron transfer processes in peptides and proteins. Systematic changes in the acidity, redox potential, and O-H bond strength of the tyrosine side chain could be induced upon substituting the phenol for pyridinol and pyrimidinol moieties.

A simple Cu-catalyzed coupling approach to substituted 3-pyridinol and 5-pyrimidinol antioxidants.

A convenient approach to 3-pyridinols and 5-pyrimidinols via a two-step Cu-catalyzed benzyloxylation/catalytic hydrogenation sequence is presented. The corresponding 3-pyridinamines and 5-pyrimidinamines can be prepared in an analogous sequence utilizing benzylamine in lieu of benzyl alcohol. The radical-scavenging ability of these derivatives are preliminarily explored and reveal that the increased acidities of the pyridinols and pyrimidinols render them susceptible to more significant kinetic solvent effects when compared to phenols.

Hock cleavage of cholesterol 5alpha-hydroperoxide: an ozone-free pathway to the cholesterol ozonolysis products identified in arterial plaque and brain tissue.

Cholesterol 5alpha-hydroperoxide, the major product of 1O2-oxidation of cholesterol, readily undergoes acid-catalyzed (Hock) cleavage of the C5-C6 bond to yield the 5,6-secosterol ketoaldehyde and the product of its intramolecular aldolization. These cholesterol oxidation products have long been thought to arise solely from ozonolysis of cholesterol, prompting the recent suggestion that ozone is produced in humans following their identification in arterial and brain tissue extracts.

Transprotection of silyl ethers of nucleosides in FeCl3 based ionic liquids.

Ionic liquid mediated deprotection of tert-butyldimethyl silyl (TBDMS) ethers derived from various primary and secondary alcohols have been studied and the reaction conditions optimized. Deprotection of the silyl ethers in FeCl3 based ionic liquids in presence of acetic anhydride yielded the acetate esters of the corresponding alcohols in good yields. The transprotection methodology was extended to the silyl ethers of nucleosides to yield the corresponding acetylated products.