Novel Platform for Predicting Drug Effects in Patients with Acromegaly: Translational Exposure-Response Evaluation of Growth Hormone-Inhibitory Effect of Octreotide after Growth Hormone-Releasing Hormone Stimulation.

Acromegaly is a chronic systemic disease characterized by facial and peripheral changes caused by soft tissue overgrowth and is associated with multiple comorbidities. Despite available surgical and medical therapies, suitable treatments for acromegaly are still lacking. Efficient drug development requires an understanding of the exposure-response (E-R) relationship based on nonclinical and early clinical studies.

Safety and efficacy of addition of sitagliptin to rapid-acting insulin secretagogues for glycemic control, including post-prandial hyperglycemia, among Japanese with type 2 diabetes mellitus.

The safety and efficacy of sitagliptin as add-on therapy to glinides, rapid-acting insulin secretagogues, were evaluated for Japanese patients with type 2 diabetes mellitus. This 52-week study consisted of a 12-week double-blind period, followed by a 40-week open-label period. During the double-blind period, patients were randomized to sitagliptin 50 mg q.

Discovery of orally available 8-aza-5-thiaProstaglandin E1 analogs as highly selective EP4 agonists.

Analogs 8-aza-16-aryl prostaglandin E(1) (PGE(1)) and 8-aza-5-thia-16-arylPGE(1) were synthesized and evaluated with respect to their subtype receptor affinity and EP4 agonist activity for the purposes of identifying subtype-selective EP4 agonists that demonstrate oral efficacy. Using an inhibition assay of lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production in rats, representative compounds were evaluated for their pharmacokinetic profiles and in vivo efficacy. Structure-activity relationships (SARs) were characterized and presented.

Discovery of an 8-aza-5-thiaProstaglandin E1 analog as a highly selective EP4 receptor agonist.

For the purpose of discovering an orally available EP4 subtype-selective agonist, a series of 8-aza prostaglandin E(1) (PGE(1)) analogs were synthesized and evaluated for their affinity for PGE(2) receptor subtypes. Additionally, the structure-activity relationships of these compounds were studied. Among the tested compounds, the 8-aza PGE(1) analog 6 and 8-aza-5-thiaPGE(1) analog 12 had highly potent EP4 receptor affinity, good functional activity, and excellent subtype-selectivity.

Role of Arg123 in light-driven anion pump mechanisms of pharaonis halorhodopsin.

Halorhodopsin (HR) acts as a light-driven chloride pump which transports a chloride ion from the extracellular (EC) to the cytoplasmic space during a photocycle reaction that includes some photointermediates initiated by illumination. To understand the chloride uptake mechanisms, we focused on a basic residue Arg123 of HR from Natronomonas pharaonis (NpHR), which is the only basic residue located in the EC half ion channel. By the measurements of the visible absorption spectra in the dark and the light-induced inward current through the membrane, it was shown that the chloride binding and transport ability of NpHR completely disappeared by the change of arginine to glutamine.

Heterologous expression of Pharaonis halorhodopsin in Xenopus laevis oocytes and electrophysiological characterization of its light-driven Cl- pump activity.

Natronomonas pharaonis halorhodopsin (pHR) is an archaeal rhodopsin functioning as an inward-directed, light-driven Cl- pump. To characterize the electrophysiological features of the Cl- pump activity of pHR, we expressed pHR in Xenopus laevis oocytes and analyzed its photoinduced Cl- pump activity using the two-electrode voltage-clamp technique. Photoinduced outward currents were observed only in the presence of Cl-, Br-, I-, NO3-, and SCN-, but not in control oocytes, indicating that photoinduced anion currents were mediated by pHR.

Interaction of the halobacterial transducer to a halorhodopsin mutant engineered so as to bind the transducer: Cl- circulation within the extracellular channel.

An alkali-halophilic archaeum, Natronomonas pharaonis, contains two rhodopsins that are halorhodopsin (phR), a light-driven inward Cl- pump and phoborhodopsin (ppR), the receptor of negative phototaxis functioning by forming a signaling complex with a transducer, pHtrII (Sudo Y. et al., J.

Design and synthesis of a selective EP4-receptor agonist. Part 4: practical synthesis and biological evaluation of a novel highly selective EP4-receptor agonist.

A practical method of synthesizing a highly selective EP4-receptor agonist 1 using Corey lactone 2 as a key intermediate was developed. Selective methanesulfonylation of the primary alcohol of the diol 8 under the newly devised conditions followed by the protection of the remaining secondary alcohol are key reactions in this new method. Further biological evaluation of 1a-b is also reported.