Graphical representation of the three different treatment stages: Users of GTZ drugs and other antidiabetic drugs classified according to first- or second-line mono- or combination therapy at the index date.

<p>For instance, to be a glitazone user in category (2), first-line non-GTZ treatment for diabetes was discontinued after 1999 when a GTZ was prescribed as second-line monotherapy. A patient could be matched to a GTZ user in category (2) if they had received an antidiabetic drug other than a GTZ (for example: Metformin) but stopped using their first-line antidiabetic treatment after 1999 and began taking another drug (for example: Sulfonylurea) as monotherapy after at least 12 months of registered follow-up.</p

IRR of PD adjusted for potential confounders.

<p>* Main analysis: IRR for the association between GTZ use and incident PD using conditional Poisson regression to control for gender, age, practice, and treatment stage</p><p>IRR of PD adjusted for potential confounders.</p

IRR of PD: GTZ-exposed group versus the other antidiabetic drug-exposed group.

<p>* Adjusted for matched variables (age, gender, practice, and treatment stage) by conditional Poisson regression analysis.</p><p>** The rate of PD for current users of GTZ was originally divided into exposed <6 months, 6–12 months, and 1–2 years, but these cells were combined to avoid small cells that could compromise anonymity. The crude rates in these three periods were all similar at between 4.36 and 4.94, so there was no suggestion of important variation in that time period.</p><p>IRR of PD: GTZ-exposed group versus the other antidiabetic drug-exposed group.</p

Thienopyrimidinone Based Sirtuin‑2 (SIRT2)-Selective Inhibitors Bind in the Ligand Induced Selectivity Pocket

Sirtuins (SIRTs) are NAD-dependent deacylases, known to be involved in a variety of pathophysiological processes and thus remain promising therapeutic targets for further validation. Previously, we reported a novel thienopyrimidinone SIRT2 inhibitor with good potency and excellent selectivity for SIRT2. Herein, we report an extensive SAR study of this chemical series and identify the key pharmacophoric elements and physiochemical properties that underpin the excellent activity observed. New analogues have been identified with submicromolar SIRT2 inhibtory activity and good to excellent SIRT2 subtype-selectivity. Importantly, we report a cocrystal structure of one of our compounds (<b>29c</b>) bound to SIRT2. This reveals our series to induce the formation of a previously reported selectivity pocket but to bind in an inverted fashion to what might be intuitively expected. We believe these findings will contribute significantly to an understanding of the mechanism of action of SIRT2 inhibitors and to the identification of refined, second generation inhibitors