Body composition data for CR and CB1Ra treatment studies.

<p>Different color curves show changes in body composition in response to different levels of CR (A) and CB1Ra (B). Changes in FFM and FM in (A) and (B) do not appear along a single pre-defined FFM-FM curve (dashed line) defined by the energy partition function [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0155674#pone.0155674.ref007" target="_blank">7</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0155674#pone.0155674.ref008" target="_blank">8</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0155674#pone.0155674.ref021" target="_blank">21</a>]. The different shapes correspond to three time points when BC measurements were taken. The colored line segments connecting data points are meant to guide the reader’s eye. Error bars represent SEM (9-10 rats).</p

Model calibration against CB1Ra data.

<p>The calibrated model shows good agreement between model simulations (black) and experimental BW (A). The fitted model trajectories show poor agreement with FFM (B) and FM (C) measurements at the three drug dose levels. Gray region indicates the intervention phase in each study. Error bars represent SEM (9-10 rats).</p

The α-free model fits BC in CR and CB1Ra BC studies.

<p>Simulations (black) of the <i>α</i>-free model show agreement with FFM (red) and FM (yellow) measurements in CR (A) and CB1Ra (B) intervention studies. Gray region indicates treatment phases in the two studies. Error bars represent SEM (9-10 rats).</p

Model calibration against CR data.

<p>The calibrated model shows good agreement between model simulations (black) and experimental BW (A), FFM (B), and FM (C) measurements at all caloric restriction levels. Gray region indicates the intervention phase in each study. Error bars represent SEM (9-10 rats).</p

The α-free model allows for estimation of body composition changes compared to the two-dimensional model.

<p>Body composition simulations of the <i>α</i>-free model (blue) can be used to estimate FM and FFM outside of measured time points, black. The two-dimensional model simulation based on the <i>α</i> function (red) is unable to accurately capture changes in FM and FFM (purple). Only data for the 30 mg/kg dose is shown, with the purple line segments meant to guide the reader’s eye. Error bars represent SEM (9-10 rats).</p

Design of a Potent CB₁ Receptor Antagonist Series: Potential Scaffold for Peripherally-Targeted Agents

Antagonism of cannabinoid-1 (CB₁) receptor signaling has been demonstrated to inhibit feeding behaviors in humans, but CB₁-mediated central nervous system (CNS) side effects have halted the marketing and further development of the lead drugs against this target. However, peripherally restricted CB₁ receptor antagonists may hold potential for providing the desired efficacy with reduced CNS side effect profiles. In this report we detail the discovery and structure–activity-relationship analysis of a novel bicyclic scaffold (<b>3</b>) that exhibits potent CB₁ receptor antagonism and oral activity in preclinical feeding models. Optimization of physical properties has led to the identification of analogues which are predicted to have reduced CNS exposure and could serve as a starting point for the design of peripherally targeted CB₁ receptor antagonists

Identification of Tetrahydropyrido[4,3‑<i>d</i>]pyrimidine Amides as a New Class of Orally Bioavailable TGR5 Agonists

Takeda G-protein-coupled receptor 5 (TGR5) represents an exciting biological target for the potential treatment of diabetes and metabolic syndrome. A new class of high-throughput screening (HTS)-derived tetrahydropyrido­[4,3-<i>d</i>]­pyrimidine amide TGR5 agonists is disclosed. We describe our effort to identify an orally available agonist suitable for assessment of systemic TGR5 agonism. This effort resulted in identification of <b>16</b>, which had acceptable potency and pharmacokinetic properties to allow for in vivo assessment in dog. A key aspect of this work was the calibration of human and dog in vitro assay systems that could be linked with data from a human ex vivo peripheral blood monocyte assay that expresses receptor at endogenous levels. Potency from the human in vitro assay was also found to correlate with data from an ex vivo human whole blood assay. This calibration exercise provided confidence that <b>16</b> could be used to drive plasma exposures sufficient to test the effects of systemic activation of TGR5