Discovery of IRAK4 Inhibitors (Zabedosertib) and .

Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in innate inflammatory processes. Here, we describe the discovery of two clinical candidate IRAK4 inhibitors, (zabedosertib) and , starting from a high-throughput screening hit derived from Bayer's compound library. By exploiting binding site features distinct to IRAK4 using an in-house docking model, liabilities of the original hit could surprisingly be overcome to confer both candidates with a unique combination of good potency and selectivity.

Discovery and In Vitro Characterization of BAY 2686013, an Allosteric Small Molecule Antagonist of the Human Pituitary Adenylate Cyclase-Activating Polypeptide Receptor.

The human pituitary adenylate cyclase-activating polypeptide receptor (hPAC-R), a class B G-protein-coupled receptor (GPCR) identified almost 30 years ago, represents an important pharmacological target in the areas of neuroscience, oncology, and immunology. Despite interest in this target, only a very limited number of small molecule modulators have been reported for this receptor. We herein describe the results of a drug discovery program aiming for the identification of a potent and selective hPAC-R antagonist.

Discovery of , a Selective CNS Penetrant Chemical Probe as Transient Receptor Potential Ankyrin 1 (TRPA1) Antagonist.

Transient receptor potential ankyrin 1 (TRPA1) is a voltage-dependent, ligand-gated ion channel, and activation thereof is linked to a variety of painful conditions. Preclinical studies have demonstrated the role of TRPA1 receptors in a broad range of animal models of acute, inflammatory, and neuropathic pain. In addition, a clinical study using the TRPA1 antagonist GRC-17536 (Glenmark Pharmaceuticals) demonstrated efficacy in a subgroup of patients with painful diabetic neuropathy.

Identification of a Benzimidazolecarboxylic Acid Derivative (BAY 1316957) as a Potent and Selective Human Prostaglandin E2 Receptor Subtype 4 (hEP4-R) Antagonist for the Treatment of Endometriosis.

The presence and growth of endometrial tissue outside the uterine cavity in endometriosis patients are primarily driven by hormone-dependent and inflammatory processes-the latter being frequently associated with severe, acute, and chronic pelvic pain. The EP4 subtype of prostaglandin E2 (PGE2) receptors (EP4-R) is a particularly promising anti-inflammatory and antinociceptive target as both this receptor subtype and the pathways forming PGE2 are highly expressed in endometriotic lesions. High-throughput screening resulted in the identification of benzimidazole derivatives as novel hEP4-R antagonists.

Discovery of selective urokinase plasminogen activator (uPA) inhibitors as a potential treatment for multiple sclerosis.

We report here the design and synthesis of a novel series of benzylamines that are potent and selective inhibitors of uPA with promising oral availability in rat. Further evaluation of one representative (ZK824859) of the new structural class showed that this compound lowered clinical scores when dosed in either acute or chronic mouse EAE models, suggesting that uPA inhibitors of this type could be useful for the treatment of multiple sclerosis.

Novel carboranyl C-glycosides for the treatment of cancer by boron neutron capture therapy.

The synthesis of the novel unprotected carboranyl C-glycosides 2 and 20-24 starting from ethynyl C-glycosides 1, 5-8, 10, and 13 is described. The new compounds are highly water-soluble and display only a very low cytotoxicity, which makes them promising candidates for use in boron neutron capture therapy for the treatment of cancer.

Novel carboranes with a DNA binding unit for the treatment of cancer by boron neutron capture therapy.

The synthesis and biological evaluation of two ortho-carborane derivatives which contain a 5,6,7-trimethoxyindole (TMI) unit for use in boron neutron capture therapy is described. The TMI moiety is known to be the DNA-binding part of the highly potent anticancer agent duocarmycin A. The ortho-carborane derivatives were prepared from amino alkynes which were bound to a protected TMI carboxylic acid.