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Using a convergent synthetic route to enable multiple points of diversity, a series of glucocorticoid receptor modulators (GRM) were profiled for potency, selectivity, and drug-like properties

Tumor necrosis factor α (TNFα) is a soluble cytokine that is directly involved in systemic inflammation through the regulation of the intracellular NF-κB and MAPK signaling pathways. The development of biologic drugs that inhibit TNFα has led to improved clinical outcomes for patients with rheumatoid arthritis and other chronic autoimmune diseases; however, TNFα has proven to be difficult to drug with small molecules. Herein, we present a two-phase, fragment-based drug discovery (FBDD) effort in which we first identified isoquinoline fragments that disrupt TNFα ligand-receptor binding through an allosteric desymmetrization mechanism as observed in high-resolution crystal structures. The second phase of discovery focused on the de novo design and optimization of fragments with improved binding efficiency and drug-like properties. The 3-indolinone-based lead presented here displays oral, in vivo efficacy in a mouse glucose-6-phosphate isomerase (GPI)-induced paw swelling model comparable to that seen with a TNFα antibody.

Glucocorticoid receptor modulators (GRM) are the first-line treatment for many immune diseases, but unwanted side effects restrict chronic dosing. However, targeted delivery of a GRM payload via an immunology antibody-drug conjugate (iADC) may deliver significant efficacy at doses that do not lead to unwanted side effects. We initiated our α-TNF-GRM ADC project focusing on identifying the optimal payload and a linker that afforded stable attachment to both the payload and antibody, resulting in the identification of the synthetically accessible maleimide-Gly-Ala-Ala linker. DAR 4 purified ADCs were shown to be more efficacious in a mouse contact hypersensitivity model than the parent α-TNF antibody. Analysis of P1NP and corticosterone biomarkers showed there was a sufficient therapeutic window between efficacy and unwanted effects. In a chronic mouse arthritis model, α-TNF-GRM ADCs were more efficacious than both the parent α-TNF mAb and an isotype control bearing the same GRM payload.

A HTS campaign identified compound 1, an excellent hit-like molecule to initiate medicinal chemistry efforts to optimize a dual ROCK1 and ROCK2 inhibitor. Substitution (2-Cl, 2-NH

We describe the design, synthesis, and structure-activity relationships (SARs) of a series of 2-aminobenzothiazole inhibitors of Rho kinases (ROCKs) 1 and 2, which were optimized to low nanomolar potencies by use of protein kinase A (PKA) as a structure surrogate to guide compound design. A subset of these molecules also showed robust activity in a cell-based myosin phosphatase assay and in a mechanical hyperalgesia in vivo pain model.

The majority of ADCs in preclinical and clinical development are for oncology indications where cytotoxic payloads are targeted to antigen-expressing cancer cells. However, the modulation of pathogenic cellular activity via ADC-mediated delivery of bioactive small molecules is also an attractive concept for non-oncology indications leading to an expanded application of the technology. Here we summarize those ADCs that have been described so far for non-oncology applications and which cover a variety of payload mechanisms beyond cell killing, from early in vitro proof-of-concept experiments to clinical trials. As our understanding of ADC technology continues to grow, it is anticipated that the development of ADCs as therapeutics for disease areas outside of oncology will also increase.

Covalent modulation of protein function can have multiple utilities including therapeutics, and probes to interrogate biology. While this field is still viewed with scepticism due to the potential for (idiosyncratic) toxicities, significant strides have been made in terms of understanding how to tune electrophilicity to selectively target specific residues. Progress has also been made in harnessing the potential of covalent binders to uncover novel biology and to provide an enhanced utility as payloads for Antibody Drug Conjugates. This perspective covers the tenets and applications of covalent binders.

Covalent modulation of protein function can have multiple utilities including therapeutics, and probes to interrogate biology. While this field is still viewed with scepticism due to the potential for (idiosyncratic) toxicities, significant strides have been made in terms of understanding how to tune electrophilicity to selectively target specific residues. Progress has also been made in harnessing the potential of covalent binders to uncover novel biology and to provide an enhanced utility as payloads for Antibody Drug Conjugates. This perspective covers the tenets and applications of covalent binders.

S1P5 is one of 5 receptors for sphingosine-1-phosphate and is highly expressed on endothelial cells within the blood-brain barrier, where it maintains barrier integrity in in vitro models (J. Neuroinflamm. 2012, 9, 133). Little more is known about the effects of S1P5 modulation due to the absence of tool molecules with suitable selectivity and drug-like properties. We recently reported that molecule A-971432 (Harris, 2010) (29 in this paper) is highly efficacious in reversing lipid accumulation and age-related cognitive decline in rats (Van der Kam , , AAIC 2014). Herein we describe the development of a series of selective S1P5 agonists that led to the identification of compound 29, which is highly selective for S1P5 and has excellent plasma and CNS exposure after oral dosing in preclinical species. To further support its suitability for in vivo studies of S1P5 biology, we extensively characterized 29, including confirmation of its selectivity in pharmacodynamic assays of S1P1 and S1P3 function in rats. In addition, we found that 29 improves blood-brain barrier integrity in an in vitro model and reverses age-related cognitive decline in mice. These results suggest that S1P5 agonism is an innovative approach with potential benefit in neurodegenerative disorders involving lipid imbalance and/or compromised blood-brain barrier such as Alzheimer's disease or multiple sclerosis.

The action of Janus kinases (JAKs) is required for multiple cytokine signaling pathways, and as such, JAK inhibitors hold promise for treatment of autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, and psoriasis. However, due to high similarity in the active sites of the four members (Jak1, Jak2, Jak3, and Tyk2), developing selective inhibitors within this family is challenging. We have designed and characterized substituted, tricyclic Jak3 inhibitors that selectively avoid inhibition of the other JAKs. This is accomplished through a covalent interaction between an inhibitor containing a terminal electrophile and an active site cysteine (Cys-909). We found that these ATP competitive compounds are irreversible inhibitors of Jak3 enzyme activity in vitro. They possess high selectivity against other kinases and can potently (IC50 < 100 nm) inhibit Jak3 activity in cell-based assays. These results suggest irreversible inhibitors of this class may be useful selective agents, both as tools to probe Jak3 biology and potentially as therapies for autoimmune diseases.

The title azulene derivatives are obtained by a linear three-step route involving the coupling of 2-cyclopentenone with various aldehydes, stereoselective epoxidation, and Lewis acid catalyzed cyclization.

A very highly diastereoselective semipinacol rearrangement of 2,3-epoxy alcohol mediated by tin-(IV) chloride at ambient temperatures is shown to be applicable to a wide variety of migrating groups including methyl, tert-butyl, cyclopropyl; vinyl, alkynyl, phenyl, and 2-furyl. A synthetically valuable feature is that a mixture of syn- and anti-epoxy alcohol affords only a single diastereoisomerically pure β-hydroxy ketone. Additional advantages of the reaction include the presence in the product of two adjacent stereocenters and the efficient creation of a new quaternary center, valuable features in the synthesis of a variety of natural products

Tricyclic keto-diols have been synthesised by a three-step annulation procedure in which hydroxyenones, prepared by the coupling of 2-cyclohexen-1-one with aldehydes, are diastereoselectively epoxidised and the syn-epoxides cyclised with tin(IV) chloride. Kinetic resolution of the hydroxyenones was achieved by enantiomeric epoxidation.

A very highly diastereoselective semipinacol rearrangement of 2,3-epoxy alcohol mediated by tin-(IV) chloride at ambient temperatures is shown to be applicable to a wide variety of migrating groups including methyl, tert-butyl, cyclopropyl; vinyl, alkynyl, phenyl, and 2-furyl. A synthetically valuable feature is that a mixture of syn- and anti-epoxy alcohol affords only a single diastereoisomerically pure β-hydroxy ketone. Additional advantages of the reaction include the presence in the product of two adjacent stereocenters and the efficient creation of a new quaternary center, valuable features in the synthesis of a variety of natural products

Automated semipreparative LC/MS systems are now well established commercially and commonly used for purification of early stage drug discovery compounds. A number of vendors have instruments on the market that are capable of reliably purifying compounds with good water/acetonitrile solubility. However, these systems often fail when the sample has poor solubility, extreme polarity, and/or poor ionization. Even in cases when substantial optimization has been done prior to purification, a certain percent of failures to recover the desired product is unavoidable. In the past, when the majority of samples run on LC/MS semipreparative systems were large combinatorial libraries, some losses in this high throughput mode were acceptable. However, now that more chemistry laboratories are making smaller more focused libraries with higher purity requirements, reliability and recovery are more crucial. This paper describes modifications made to customize an MS-triggered semipreparative LC/MS system in order to ensure improved reliability and recovery of products from traditional medicinal chemistry as well as combinatorial libraries.

Tricyclic keto-diols have been synthesised by a three-step annulation procedure in which hydroxyenones, prepared by the coupling of 2-cyclohexen-1-one with aldehydes, are diastereoselectively epoxidised and the syn-epoxides cyclised with tin(IV) chloride. Kinetic resolution of the hydroxyenones was achieved by enantiomeric epoxidation.

Tricyclic keto diols have been synthesised by a new, three-step annulation procedure in which hydroxyenones, prepared by the coupling of 2-cyclohexen-1-one with aldehydes, are diastereoselectively epoxidised and the syn-epoxides cyclised with tin(IV) chloride.