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Toll-like receptor (TLR) 7 and TLR8 are endosomal sensors of the innate immune system that are activated by GU-rich single stranded RNA (ssRNA). Multiple genetic and functional lines of evidence link chronic activation of TLR7/8 to the pathogenesis of systemic autoimmune diseases (sAID) such as Sjögren's syndrome (SjS) and systemic lupus erythematosus (SLE). This makes targeting TLR7/8-induced inflammation with small-molecule inhibitors an attractive approach for the treatment of patients suffering from systemic autoimmune diseases. Here, we describe how structure-based optimization of compound 2 resulted in the discovery of 34 (MHV370, ( S )-N-(4-((5-(1,6-dimethyl-1 H -pyrazolo[3,4- b ]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1 H -pyrazolo[4,3- c ]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide). Its in vivo activity allows for further profiling toward clinical trials in patients with autoimmune disorders, and a Phase 2 proof of concept study of MHV370 has been initiated, testing its safety and efficacy in patients with Sjögren's syndrome and mixed connective tissue disease., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

Antagonism of the Toll-like receptors (TLRs) 7 and TLR8 has been hypothesized to be beneficial to patients suffering from autoimmune conditions. A phenotypic screen for small molecule antagonists of TLR7/8 was carried out in a murine P4H1 cell line. Compound 1 was identified as a hit that showed antagonistic activity on TLR7 and TLR8 but not TLR9, as shown on human peripheral blood mononuclear cells (hPBMCs). It was functionally cross reactive with mouse TLR7 but lacked oral exposure and had only modest potency. Chemical optimization resulted in 2, which showed in vivo efficacy following intraperitoneal administration. Further optimization resulted in 8 which had excellent in vitro activity, exposure and in vivo activity. Additional work to improve physical properties resulted in 15, an advanced lead that had favorable in vitro and exposure properties. It was further demonstrated that activity of the series tracked with binding to the extracellular domain of TLR7 implicating that the target of this series are endosomal TLRs rather than downstream signaling pathways., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven largely by target-based mutations in the GyrA/ParC quinolone resistance determining region, have eroded the utility and threaten the future use of this vital class of antibiotics. Herein we describe the discovery and optimization of a series of 4-(aminomethyl)quinolin-2(1 H )-ones, exemplified by 34 , that inhibit bacterial DNA gyrase and topoisomerase IV and display potent activity against ciprofloxacin-resistant Gram-negative pathogens. X-ray crystallography reveals that 34 occupies the classical quinolone binding site in the topoisomerase IV-DNA cleavage complex but does not form significant contacts with residues in the quinolone resistance determining region.

The farnesoid X receptor (FXR) is a nuclear receptor that acts as a master regulator of bile acid metabolism and signaling. Activation of FXR inhibits bile acid synthesis and increases bile acid conjugation, transport, and excretion, thereby protecting the liver from the harmful effects of bile accumulation, leading to considerable interest in FXR as a therapeutic target for the treatment of cholestasis and nonalcoholic steatohepatitis. We identified a novel series of highly potent non-bile acid FXR agonists that introduce a bicyclic nortropine-substituted benzothiazole carboxylic acid moiety onto a trisubstituted isoxazole scaffold. Herein, we report the discovery of 1 (tropifexor, LJN452), a novel and highly potent agonist of FXR. Potent in vivo activity was demonstrated in rodent PD models by measuring the induction of FXR target genes in various tissues. Tropifexor has advanced into phase 2 human clinical trials in patients with NASH and PBC.

Systematic SAR optimization of the GPR119 agonist lead 1, derived from an internal HTS campaign, led to compound 29. Compound 29 displays significantly improved in vitro activity and oral exposure, leading to GLP1 elevation in acutely dosed mice and reduced glucose excursion in an OGTT study in rats at doses ⩾10 mg/kg., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Screening hit 5 was identified in a biochemical screen for GPR119 agonists. Compound 5 was structurally novel, displayed modest biochemical activity and no oral exposure, but was structurally distinct from typical GPR119 agonist scaffolds. Systematic optimization led to compound 36 with significantly improved in vitro activity and oral exposure, to elevate GLP1 acutely in an in vivo mouse model at a dose of 10mg/kg., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Serratezomine A is a member of the structurally diverse class of compounds known as the Lycopodium alkaloids. The key supporting studies and successful total synthesis of serratezomine A are described in this account. Significant features of the synthesis include the first application of free radical mediated vinyl amination and Hwu's oxidative allylation in a total synthesis and an intramolecular lactonization via a transannular S(N)i reaction. Minimal use of protecting groups and the highly diastereoselective formation of a hindered, quaternary stereocenter using an umpolung allylation are also highlights from a strategy perspective. Observation of quaternary carbon epimerization via a retro-Mannich/Mannich sequence highlights the additional challenge presented by the axial alcohol at C8 in serratezomine A.

The first total synthesis of (+)-serratezomine A is described. Key aspects of the synthesis include (a) the first deployment of free-radical-mediated vinyl amination (an intramolecular alkyne aminostannation) in a complex target synthesis, (b) the use of a beta-stannyl enamine as the lynchpin for convergent assembly of the natural product backbone, (c) the use of an oxidative allylation promoted by cerium(IV) (CAN) to establish the all-carbon quaternary chiral center with the proper configuration, and (d) an intramolecular substitution reaction to form the sensitive bridging lactone. Overall, 15 steps (longest linear sequence) are required to prepare the natural product from a commercially available aldehyde, and assembly of the contiguous array of six stereocenters is accomplished with high stereocontrol.

A novel series of benzo[a]carbazole-based small molecule agonists of the thrombopoietin (Tpo) receptor is reported. Starting from a 3.4 microM high throughput screen hit, members of this series have been identified which are full agonists with functional potency <50 nM and oral bioavailability in mice.

The lead optimization of a novel series of benzo[a]carbazole-based small molecule agonists of the thrombopoietin (Tpo) receptor is reported. The chemical instability of the dihydro-benzo[a]carbazole lead 2 was successfully addressed in the design and evaluation of compounds which also demonstrated improved potency compared to 2. Members of the scaffold have been identified which are full agonists that demonstrate cellular functional potency <50 nM. Analog 21 demonstrates equivalent efficacy in the human megakaryocyte differentiation (CFU-mega) assay compared to Eltrombopag.

We report a novel series of noncovalent inhibitors of cathepsin S. The synthesis of the peptidomimetic scaffold is described and structure-activity relationships of P3, P1, and P1' subunits are discussed. Lead optimization to a non-peptidic scaffold has resulted in a new class of potent, highly selective, and orally bioavailable cathepsin S inhibitors.

Atopic dermatitis (AD) is a common chronic skin inflammatory disease. Long-term use of topical corticosteroids in skin inflammation poses risks of systemic and local side effects. The NF-kappaB transcription factor family plays a central role in the progression and maintenance of AD. This study explores the possibility of using topical NF-kappaB Decoy as a novel therapeutic alternative for targeting Th1/Th2-driven skin inflammation in experimental AD. A high-affinity, topical NF-kappaB Decoy developed for human efficacy demonstrates: (i) efficient NF-kappaB Decoy penetration in pig skin, (ii) NF-kappaB Decoy nuclear localization in keratinocytes and key immune cells, and (iii) potent "steroid-like" efficacy in a chronic dust-mite antigen skin inflammation treatment model. NF-kappaB Decoy exerts its anti-inflammatory action through the effective inhibition of essential regulators of inflammation and by induction of apoptosis of key immune cells. Unlike betamethasone valerate (BMV), long-term NF-kappaB Decoy treatment does not induce skin atrophy. Moreover, topical NF-kappaB Decoy, in contrast to BMV, restores compromised stratum corneum integrity and barrier function. Steroid withdrawal causes rapid rebound of inflammation, while the NF-kappaB Decoy therapeutic benefit was maintained for weeks. Thus, topical NF-kappaB Decoy provides a novel mechanism of reducing chronic skin inflammation with improved skin homeostasis and minimal side effects.

The first examples of the azacyclopentenyl carbinyl radical isomerization are described within a series of enantiomerically enriched 2-substituted indolines, a substructure found extensively in both heterocyclic and natural product chemistry. The isomerization was identified by the varying loss of enantiomeric enrichment (ee) of imines during aryl radical cyclizations to azomethine nitrogen. Independent modification of the steric and electronic nature of the ring substituents revealed the full spectrum of sensitivity to these variables and ultimately defined the use of these effects as gating elements. An example is also given in which a 1,4-amino group transfer is effected via the isomerization mechanism. Analogies are drawn between the title isomerization and the azacyclopropyl carbinyl radical isomerization that has been studied in both chemical and biological contexts.

Colloidal silica particles were deposited on a glass substrate to produce high-capacity porous supports for high-density DNA probe arrays. Porous surfaces were used to increase the addressable surface area and number of probes available for hybridization. Surfaces derived from 70-100 nm size particles deposited in films from 0.15 to 2 microns thick exhibited excellent performance in light-directed oligonucleotide synthesis. Evaluation of these substrates in a genotyping assay is reported.