Discovery of Clinical Candidate AZD5462, a Selective Oral Allosteric RXFP1 Agonist for Treatment of Heart Failure.

Optimization of the highly potent and selective, yet metabolically unstable and poorly soluble hRXFP1 agonist AZ7976 led to the identification of the clinical candidate, AZD5462. Assessment of RXFP1-dependent cell signaling demonstrated that AZD5462 activates a highly similar panel of downstream pathways as relaxin H2 but does not modulate relaxin H2-mediated cAMP second messenger responsiveness. The therapeutic potential of AZD5462 was assessed in a translatable cynomolgus monkey heart failure model. Following 8 weeks of treatment with AZD5462, robust improvements in functional cardiac parameters including LVEF were observed at weeks 9, 13, and 17 without changes in heart rate or mean arterial blood pressure. AZD5462 was well tolerated in both rat and cynomolgus monkey and has successfully completed phase I studies in healthy volunteers. In summary, AZD5462 is a small molecule pharmacological mimetic of relaxin H2 signaling at RXFP1 and holds promise as a potential therapeutic approach to treat heart failure patients.

Discovery of evocalcet, a next-generation calcium-sensing receptor agonist for the treatment of hyperparathyroidism.

The calcium-sensing receptor (CaSR) plays an important role in sensing extracellular calcium ions and regulating parathyroid hormone secretion by parathyroid gland cells, and the receptor is a suitable target for the treatment of hyperparathyroidism. Cinacalcet hydrochloride is a representative CaSR agonist which widely used for the hyperparathyroidism. However, it has several issues to clinical use, such as nausea/vomiting and strong inhibition of CYP2D6. We tried to improve these issues of cinacalcet for a new pharmaceutical agent as a preferable CaSR agonist. Optimization from cinacalcet resulted in the identification of pyrrolidine compounds and successfully led to the discovery of evocalcet as an oral allosteric CaSR agonist. Evocalcet, which exhibited highly favorable profiles such as CaSR agonistic activity and good DMPK profiles, will provide a novel therapeutic option for secondary hyperparathyroidism.

Gram-negative bacterial ATP-binding cassette protein exporter family and diverse secretory proteins.

Protein translocation to the extracellular space is essential for the invasion, colonization, and survival of pathogenic gram-negative bacteria within a host organism. In addition to the N-terminal signal sequence-dependent secretion system, which is specific for protein transport to the periplasmic space, there are five major systems (type I, II, III, IV, and V) that are known to be involved in protein secretion into the extracellular space. Of the systems, the type I pathway, which is composed of three membrane components including an ATP-binding cassette (ABC) protein, translocates proteins into the extracellular space from the cytosol by directly using the energy generated from ATP hydrolysis, and therefore, the system is a member of the ABC transporter family and is also known as the ABC exporter. To date, ABC exporters have been discovered to be involved in the secretion of a wide variety of exoproteins including RTX (repeats-in-toxin) toxins, cell surface layer proteins, proteases, lipases, bacteriocins, heme-acquisition proteins, and nodulation-related proteins such as the exoglucanases of gram-negative bacteria. A secretory protein and its associated specific ABC exporter are encoded in the same gene cluster in most cases, and ABC exporters show substrate specificity for secretion. Consequently, ABC exporters are present based primarily on the number of secretory protein genes. A secretion signal is situated in the C-terminal region of secretory proteins, however, the characteristics of the secretion signal are not fully understood. Secretory substrates and their linked ABC exporters are reviewed in the following paper.