Development of a Scalable Synthesis of Mevidalen (LY3154207), an Orally Available Positive Allosteric Modulator of the Human Dopamine D1 Receptor

2020 ◽  
Vol 24 (11) ◽  
pp. 2549-2564
Author(s):  
Jeffery Richardson ◽  
Kevin P. Cole ◽  
Amy C. DeBaillie ◽  
Junliang Hao ◽  
Jared Piper ◽  
...  
Keyword(s):  
Dopamine D1 Receptor ◽  
D1 Receptor ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Scalable Synthesis

scholarly journals Intracellular Binding Site for a Positive Allosteric Modulator of the Dopamine D1 Receptor

2018 ◽  
Vol 94 (4) ◽  
pp. 1232-1245 ◽  
Author(s):  
Xushan Wang ◽  
Beverly A. Heinz ◽  
Yue-Wei Qian ◽  
Joan H. Carter ◽  
Robert A. Gadski ◽  
...  
Keyword(s):  
Binding Site ◽  
Dopamine D1 Receptor ◽  
D1 Receptor ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Intracellular Binding

scholarly journals Phase 1 randomized study on the safety, tolerability, and pharmacodynamic cognitive and electrophysiological effects of a dopamine D1 receptor positive allosteric modulator in patients with schizophrenia

2020 ◽  
Author(s):  
Amit Desai ◽  
Lauren Benner ◽  
Ruishan Wu ◽  
Lev Gertsik ◽  
Paul Maruff ◽  
...  
Keyword(s):  
Steady State ◽  
Phase Synchronization ◽  
Phase 1 ◽  
Event Related Potentials ◽  
D1 Receptor ◽  
Sample Size Determination ◽  
Allosteric Modulator ◽  
Cognitive Tests ◽  
Positive Allosteric Modulator ◽  
Related Potentials

AbstractASP4345, a novel dopamine D1 receptor positive allosteric modulator, is being evaluated for the treatment of cognitive impairment associated with schizophrenia (CIAS). This phase 1 multiple ascending-dose study (NCT02720263) assessed the safety, tolerability, and pharmacodynamics of ASP4345 in patients with schizophrenia/schizoaffective disorder. Pharmacodynamic assessments were Cogstate cognitive tests and electrophysiological biomarkers, including gamma-band power and phase synchronization in response to 40-Hz auditory steady-state stimulation, as well as mismatch negativity (MMN) and P3a event-related potentials. The sample size determination was based on standard practice in assessing safety and tolerability of a new chemical entity. Data were summarized by conversion of this data into effect sizes using descriptive and inferential statistics. A total of 36 randomized patients received ASP4345 (3, 15, 50, and 150 mg; n = 9 each dose) and 12 patients received placebo. Patients in the ASP4345 group experienced 73 treatment-emergent adverse events (TEAEs) and 34 TEAEs were reported for the placebo group. The most common TEAEs were headache and somnolence and nearly all TEAEs were mild in severity. No changes in mood or self-reports of suicidal ideation/behavior were observed. Improvements in performance on cognitive tests were noted, which suggests a potential improvement in psychomotor function and visual attention. Furthermore, positive changes in neurophysiological biomarkers (auditory steady-state response [ASSR] and MMN) suggest improvement in information processing. The findings need to be confirmed in studies with a larger patient population. Nonetheless, the trends in safety and pharmacodynamic data support further clinical development of ASP4345 for the treatment of CIAS.

Correction: Structural modeling and role of HAX-1 as a positive allosteric modulator of human serine protease HtrA2

2020 ◽  
Vol 477 (2) ◽  
pp. 459-459
Author(s):  
Lalith K. Chaganti ◽  
Shubhankar Dutta ◽  
Raja Reddy Kuppili ◽  
Mriganka Mandal ◽  
Kakoli Bose
Keyword(s):  
Serine Protease ◽  
Structural Modeling ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator
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