A series of carboxyamido-propanyl analogs is described as antiviral agents for inhibition of the replication of hRSV and hMPV. Human Respiratory Syncytial Virus (hRSV, RSV) belongs to the family and the subfamily that are significant human and animal pathogens. After hRSV, hMPV (metapneumovirus) is the second most common cause of lower respiratory infection in young children. Therefore, inhibition of hRSV and hMPV is an important approach for the potential treatment of respiratory viral infections.

Poly-(ADP-ribose) polymerases (PARPs) constitute a family of nuclear enzymes that play critical roles in the DNA damage response and the preservation of genomic stability. Beyond DNA repair, PARPs are increasingly recognized as key regulators of oxidative stress, inflammatory processes, viral pathogenesis, and glucose homeostasis. This disclosure describes the synthesis and therapeutic application of novel compounds designed for the treatment of diseases mediated by aberrant PARP activity.

A library of 66 small molecules targeting IRE1α were designed using a molecular docking approach and prepared by a two-step reaction sequence using diverse substrates. All compounds utilized a 1-amino-4-bromonaphthalene core that was modified via Suzuki coupling with boronic acids to form intermediates that were carbamoylated to form urea-linked inhibitor candidates. We developed a 3 DoE approach for the Suzuki coupling reaction that was optimized with 216 reactions via HTE. By screening the purified compounds in a tunicamycin-induced ER stress assay with ARPE-19 cells and quantifying their kinase inhibition activity by RT-qPCR, we identified 14 derivatives with the potential for IRE1α inhibition. IC assays showed that six of the compounds displayed IRE1α inhibition alike KIRA6, a standard in IRE1α inhibition, with three of the leads possessing improved IC. Viability screens indicated that the best IRE1α inhibitors were not cytotoxic in the working concentrations and displayed improved protection from apoptosis compared to KIRA6.

Chikungunya virus (CHIKV) results in debilitating chronic pain in nearly half of those infected. With no FDA approved small molecule-based therapeutics available, we screened compounds to reveal quinazolinone ()- with a modest 0.3 log reduction of CHIKV titer and no significant toxicity (CC > 40 μM). Five scaffold regions were surveyed to improve the titer reduction efficiency. Chemistry was established to preserve the enantiopurity of 2-piperidinyl-containing analogues, affording ()- (BDGR-651) which reduced CHIKV titer in normal human dermal fibroblasts by 4.1 log at 10 μM (EC = 0.86 μM). Excellent solubility and mouse microsomal and plasma stabilities were observed, and confocal microscopy of infected Vero E6 cells treated with ()- showed a dose-dependent protective effect. A narrow selectivity index prevented evaluation, but the study showed that antiencephalitic alphavirus quinazolinones could be reengineered to inhibit CHIKV, an arthritogenic virus, against which previous analogues showed no significant activity.

Chitinase-3-like protein 1 (CHI3L1), a glycoprotein implicated in inflammation and cancer, has emerged as a therapeutic target for glioblastoma (GBM). CHI3L1 contributes to tumor progression and immune evasion by promoting STAT3 signaling and mesenchymal transition. To identify small-molecule CHI3L1 inhibitors, a structure-based 3D pharmacophore model was developed and applied to virtually screen over 4.4 million compounds. We selected 35 candidates for experimental evaluation. Binding validation via MST confirmed dose-dependent CHI3L1 interactions for two compounds, and , with dissociation constants ( ) of 6.8 μM and 22 μM, respectively. These CHI3L1 affinities were further supported by SPR-based screening. In 3D GBM spheroid models, compound reduced spheroid viability and attenuated phospho-STAT3 levels, consistent with CHI3L1 pathway disruption. Compared to the previously reported CHI3L1 inhibitors, compound demonstrates superior CNS pharmacokinetics, inhibition of STAT3 and angiogenesis, and enhanced efficacy in GBM spheroids, establishing it as a more translationally viable scaffold.

NUAK1 is a protein kinase with various cellular functions including cell proliferation, migration and adhesion. NUAK1 has also been implicated in tau phosphorylation and stabilization leading to interest in this kinase as a therapeutic target for neurodegenerative disease. Herein, we describe the optimization of the CDK2 inhibitor NU6140 to the potent and selective NUAK1 inhibitor ARUK2010694, with a significantly improved mouse plasma half-life. Further development of this series also led to the discovery of ARUK2010489, a highly brain penetrant NUAK1 inhibitor (unbound brain/plasma ratio in mice (K) of 2.29) that displays no CDK2 activity, applicable for CNS pharmacological studies.

Two complementary PROTAC classesbenzimidazole-anchored degraders of LRRK2 and pyrrolopyridine-based scaffolds for tau and α-synuclein clearancedemonstrate subnanomolar degradation potency, improved SAR over phthalimide comparators, and translational positioning for Parkinson's disease and tauopathies. Together, they highlight the therapeutic convergence of chemically differentiated anchors and robust degradation assays in advancing CNS-targeted protein degradation modalities.

KIF18A is an ATP-dependent, plus end-directed mitotic kinesin that facilitates chromosome alignment and spindle microtubule dynamics during mitosis. Certain cancer types may be particularly vulnerable to KIF18A inhibition, specifically cancer cells with high levels of chromosomal instability (CIN). As part of efforts to identify KIF18A inhibitors, silicon atom replacement was explored to improve ligand-KIF18A interactions and ADME parameters. This tactic resulted in the discovery of a series of silapiperidine-containing KIF18A inhibitors and culminated in the identification and characterization of . is a potent KIF18A inhibitor with a high degree of kinesin selectivity, favorable and ADME properties, and robust efficacy in the OVCAR-3 cell-derived xenograft (CDX) model. A high-resolution crystal structure of the KIF18A-tubulin complex and an experimentally guided model of bound to the complex are provided, supporting future structure-based drug design of KIF18A inhibitors.

-Methyladenosine methylation (mA) is the most common type of RNA modification and is catalyzed primarily by the METTL3-METTL14 methyltransferase complex. METTL3 is considered a promising target for the treatment of acute myeloid leukemia (AML). However, only a few METTL3 inhibitors targeting the catalytic activity have been developed recently. Herein we report a series of novel METTL3 inhibitors bearing a pyridin-2-(1)-one moiety by structure-based drug design. Among these, compound exhibits potent inhibitory activity against METTL3 (IC = 50 nM). Compound shows moderate metabolic stability in mouse and human liver microsomes. Meanwhile, in MV411 and SKM1 cell lines, compound is able to potently inhibit cell proliferation. These results make compound a promising lead compound for further optimization.

The invention discloses novel NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inhibitors featuring a 2-pyrazolo-[3,4-]-thiazole scaffold. These NLRP3 inhibitors exhibit significant potential as therapeutic candidates for neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease.

The invention in this patent application relates to compounds having structures represented generally herein by formula 1. These compounds are modulators of alpha 4 beta 7 integrin and may provide useful treatment for several inflammatory conditions such as inflammatory bowel diseases, including ulcerative colitis and Crohn's disease.

This patent highlight describes the development of novel substituted -arylquinoline-4-carboxamide derivatives as potent, selective antagonists of the prostaglandin F (FP) receptors. The synthetic methods, pharmacological properties and therapeutic potential of these novel FP antagonists are disclosed in this patent.

Provided herein are novel cyanotriazole compounds, pharmaceutical compositions, use of such compounds in treating Chagas disease, leishmaniasis and human African trypanosomiasis (HAT), and processes for preparing such compounds.

Rapaglutin A (RgA) is a potent pan-class I glucose transporter (GLUT) inhibitor identified from the rapafucin library. However, its development is hindered by plasma instability due to the rapid hydrolysis of lactone moieties by carboxylesterases, especially in rodents. To improve its stability, we designed and synthesized RgA analogues in which the lactones were substituted with more stable lactams. We found that substitution of either lactone-enhanced plasma stability, while dual lactam replacement produced the greatest improvement in mouse plasma, which has a high esterase activity. Importantly, the lactam analogues retained most of the inhibitory activity of the parent RgA against GLUT in DLD1 cells. This approach offers a promising strategy to enhance the plasma stability of RgA without significantly compromising its activity, with potential applicability across the rapafucin class of macrocycles.

This patent application discloses a series of bicyclic peptides targeting the Interleukin-23 receptor (IL-23R), as represented by Formula I. These peptides exhibit significant therapeutic potential, particularly for the treatment of inflammatory conditions, and hold promise for benefiting patients with inflammatory bowel disease (IBD).

Recent advances in targeted protein degradation and kinase modulation highlight therapeutic versatility across disease areas. Keap1-based degraders eliminate oncogenic KRAS and androgen receptor in cancer, antifolate-idasanutlin hybrids degrade DHFR-TS to overcome antifolate resistance, and PLK1 inhibition suppresses NLRP3 inflammasome activation to improve cardiac outcomes. Together, these innovations expand degrader and kinase-targeting strategies into oncology, infectious disease, and inflammatory cardiology.

[This corrects the article DOI: 10.1021/acsmedchemlett.3c00452.].

Provided herein are novel piperidinylphenylcarbonitrile derivatives as QPCT and QPCTL inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.

Relaxin-3, a neuropeptide in the insulin/relaxin superfamily, signals via the G protein-coupled receptor RXFP3 and regulates motivated behaviors such as feeding, arousal, exploration, and reward-seeking. Despite its therapeutic promise for neuropsychiatric and metabolic disorders, the complex two-chain (A and B), three-disulfide structure of relaxin-3 hampers drug development. To overcome this, simplified B-chain-only analogues have been explored and developed, including the stapled RXFP3 agonist H3B10-27-(13/17αF) and the linear antagonist H3B1-22R. Here, we report a novel stapled antagonist, H3B10-22R-(13/17αF), a 14-residue single-chain peptide with high RXFP3 selectivity and binding affinity, enhanced helicity and antagonist potency, and 12-fold improved serum stability compared to linear unstructured H3B1-22R, the current best RXFP3 antagonist. Importantly, H3B10-22R-(13/17αF) significantly inhibited RXFP3 agonist-induced food intake in rats, confirming its efficacy. These results establish H3B10-22R-(13/17αF) as a potent, stable, and drug-like RXFP3 antagonist, supporting its further development as a therapeutic candidate for feeding disorders (e.g., obesity).

Pregabalin and gabapentin are currently first-line treatments for neuropathic pain, but common adverse effects such as dizziness and somnolence frequently lead to treatment discontinuation. To find new drugs that mitigate CNS adverse effects while maintaining good efficacy, more than 50 tricyclic GABA derivative compounds were screened and HSK16149 (compound ) was selected in the present study. Further evaluation revealed that HSK16149 had a good potent binding affinity to the Ca channel α-δ subunits (IC = 3.96 nM) and an AUC of 13,200 ng·h/mL which was obviously higher than the control drug pregabalin. HSK16149 also demonstrated superior antihypersensitivity or antiallodynic/hyperalgesic effects compared to the commonly used pregabalin as the control and has the potential to minimize CNS side effects with good tolerability. Based on its exceptional preclinical characteristics, HSK16149 was chosen for further development to provide a more effective and safer drug for patients enduring neuropathic pain.

The invention in this patent application relates to heterocyclic compounds represented herein generally by formula 1. These compounds are inhibitors of stearoyl-coenzyme A desaturases (SCD1 and/or SCD5) and may provide a useful treatment for neurological disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) as well as primary brain cancer such as glioblastoma (GBM).