Discovery of AZD-2098 and AZD-1678, two potent and bioavailable CCR4 receptor antagonists

N-(5-Bromo-3-methoxypyrazin-2-yl)-5-chlorothiophene-2-sulfonamide 1 was identified as a hit in a CCR4 receptor antagonist high throughput screen (HTS) of a sub-set of the AstraZeneca compound bank. As a hit with a lead-like profile, it was an excellent starting point for a CCR4 receptor antagonist program and enabled the rapid progression through the Lead Identification and Lead Optimization phases resulting in the discovery of two bioavailable CCR4 receptor antagonist candidate drugs

Discovery of a Potent, Orally Bioavailable PI4KIII beta Inhibitor (UCB9608) Able To Significantly Prolong Allogeneic Organ Engraftment in Vivo

The primary target of a novel series of immunosuppressive 7-piperazin-1-ylthiazolo[5,4- d]pyrimidin-5-amines was identified as the lipid kinase, PI4KIIIβ. Evaluation of the series highlighted their poor solubility and unwanted off-target activities. A medicinal chemistry strategy was put in place to optimize physicochemical properties within the series, while maintaining potency and improving selectivity over other lipid kinases. Compound 22 was initially identified and profiled in vivo, before further modifications led to the discovery of 44 (UCB9608), a vastly more soluble, selective compound with improved metabolic stability and excellent pharmacokinetic profile. A co-crystal structure of 44 with PI4KIIIβ was solved, confirming the binding mode of this class of inhibitor. The much-improved in vivo profile of 44 positions it as an ideal tool compound to further establish the link between PI4KIIIβ inhibition and prolonged allogeneic organ engraftment, and suppression of immune responses in vivo.status: publishe

Discovery of a Potent, Orally Bioavailable PI4KIIIβ Inhibitor (UCB9608) Able To Significantly Prolong Allogeneic Organ Engraftment <i>in Vivo</i>

The primary target of a novel series of immuno­suppressive 7-piperazin-1-yl­thiazolo­[5,4-<i>d</i>]­pyrimidin-5-amines was identified as the lipid kinase, PI4KIIIβ. Evaluation of the series highlighted their poor solubility and unwanted off-target activities. A medicinal chemistry strategy was put in place to optimize physico­chemical properties within the series, while maintaining potency and improving selectivity over other lipid kinases. Compound <b>22</b> was initially identified and profiled <i>in vivo</i>, before further modifications led to the discovery of <b>44</b> (UCB9608), a vastly more soluble, selective compound with improved metabolic stability and excellent pharmaco­kinetic profile. A co-crystal structure of <b>44</b> with PI4KIIIβ was solved, confirming the binding mode of this class of inhibitor. The much-improved <i>in vivo</i> profile of <b>44</b> positions it as an ideal tool compound to further establish the link between PI4KIIIβ inhibition and prolonged allogeneic organ engraftment, and suppression of immune responses <i>in vivo</i>

Discovery of a Potent, Orally Bioavailable PI4KIIIβ Inhibitor (UCB9608) Able To Significantly Prolong Allogeneic Organ Engraftment <i>in Vivo</i>

The primary target of a novel series of immuno­suppressive 7-piperazin-1-yl­thiazolo­[5,4-<i>d</i>]­pyrimidin-5-amines was identified as the lipid kinase, PI4KIIIβ. Evaluation of the series highlighted their poor solubility and unwanted off-target activities. A medicinal chemistry strategy was put in place to optimize physico­chemical properties within the series, while maintaining potency and improving selectivity over other lipid kinases. Compound <b>22</b> was initially identified and profiled <i>in vivo</i>, before further modifications led to the discovery of <b>44</b> (UCB9608), a vastly more soluble, selective compound with improved metabolic stability and excellent pharmaco­kinetic profile. A co-crystal structure of <b>44</b> with PI4KIIIβ was solved, confirming the binding mode of this class of inhibitor. The much-improved <i>in vivo</i> profile of <b>44</b> positions it as an ideal tool compound to further establish the link between PI4KIIIβ inhibition and prolonged allogeneic organ engraftment, and suppression of immune responses <i>in vivo</i>