BACE1 is a key protease controlling the formation of amyloid , a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academiaandindustry.Herein,wereportthenonclinicalandearlyclinicaldevelopmentofLY2886721,aBACE1activesiteinhibitorthatreached phase 2 clinical trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid  lowering in nonclinical animal models. Similar potent and persistent amyloid  lowering was observed in plasma and lumbar CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of amyloid lowering and as an attractive target for potential disease modification therapy in AD.
Clinical
development of catechol-based orthosteric agonists of
the dopamine D1 receptor has thus far been unsuccessful due to multiple
challenges. To address these issues, we identified LY3154207 (3) as a novel, potent, and subtype selective human D1 positive
allosteric modulator (PAM) with minimal allosteric agonist activity.
Conformational studies showed LY3154207 adopts an unusual boat conformation,
and a binding pose with the human D1 receptor was proposed based on
this observation. In contrast to orthosteric agonists, LY3154207 showed
a distinct pharmacological profile without a bell-shaped dose-response
relationship or tachyphylaxis in preclinical models. Identification
of a crystalline form of free LY3154207 from the discovery lots was
not successful. Instead, a novel cocrystal form with superior solubility
was discovered and determined to be suitable for development. This
cocrystal form was advanced to clinical development as a potential
first-in-class D1 PAM and is now in phase 2 studies for Lewy body
dementia.
The 3-aminoquinzolinediones represent a new series of antibacterial agents structurally related to the fluoroquinolones. They are inhibitors of bacterial gyrase and topoisomerase IV and demonstrate clinically useful antibacterial activity against fastidious Gram-negative and Gram-positive organisms, including multidrug- and fluoroquinolone-resistant organisms. These agents also demonstrate in vivo efficacy in murine systemic infection models.
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