Compound 4 (PF-04971729) belongs to a new class of potent and selective sodium-dependent glucose cotransporter 2 inhibitors incorporating a unique dioxa-bicyclo[3.2.1]octane (bridged ketal) ring system. In this paper we present the design, synthesis, preclinical evaluation, and human dose predictions related to 4. This compound demonstrated robust urinary glucose excretion in rats and an excellent preclinical safety profile. It is currently in phase 2 clinical trials and is being evaluated for the treatment of type 2 diabetes.

Blackberries are rich in polyphenols, including anthocyanins. Polyphenols are hypothesized to have biological activities that may impact positively on human health. In these studies, an anthocyanin-rich extract from Hull blackberries grown in Kentucky was obtained and fully characterized in terms of total anthocyanin and phenolic content, polymeric color, anthocyanin composition, and total antioxidant capacity. In vitro cell culture studies showed that the blackberry extract inhibited HT-29 colon tumor cell growth in a concentration-dependent manner with 49.2 microg of total anthocyanins/mL inhibiting HT-29 cell growth up to 66% at 72 hours. Likewise, in a concentration-dependent manner, total anthocyanin concentrations in the range of 0-40 microg/mL suppressed both high-dose (10 microg/mL) and low-dose (0.1 microg/mL) lipid A-induced interleukin-12 release from mouse bone marrow-derived dendritic cells. These results suggest that Hull blackberry extract (HBE) has potent antioxidant, antiproliferative, and anti-inflammatory activities and that HBE-formulated products may have the potential for the treatment and/or prevention of cancer and/or other inflammatory diseases.

Ni-NPs can be used to bind strongly to his-tag proteins. This system was demonstrated to have potential applications in vaccine delivery for enhancing immune responses to protein-based vaccines.

The identification of potent, highly selective orally bioavailable ghrelin receptor inverse agonists from a spiro-azetidino-piperidine series is described. Examples from this series have promising in vivo pharmacokinetics and increase glucose-stimulated insulin secretion in human whole and dispersed islets. A physicochemistry-based strategy to increase lipophilic efficiency for ghrelin receptor potency and retain low clearance and satisfactory permeability while reducing offtarget pharmacology led to the discovery of 16h. Compound 16h has a superior balance of ghrelin receptor pharmacology and off-target selectivity. On the basis of its promising pharmacological and safety profile, 16h was advanced to human clinical trials.

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