Andy Mead

A translational pharmacology approach to understanding the predictive value of abuse potential assessments.

Within the drug development industry the assessment of abuse potential for novel molecules involves the generation and review of data from multiple sources, ranging from in-vitro binding and functional assays through to in-vivo nonclinical models in mammals, as well as collection of information from studies in humans. This breadth of data aligns with current expectations from regulatory agencies in both the USA and Europe. To date, there have been a limited number of reviews on the predictive value of individual models within this sequence, but there has been no systematic review on how each of these models contributes to our overall understanding of abuse potential risk. To address this, we analyzed data from 100 small molecules to compare the predictive validity for drug scheduling status of a number of models that typically contribute to the abuse potential assessment package. These models range from the assessment of in-vitro binding and functional profiles at receptors or transporters typically associated with abuse through in-vivo models including locomotor activity, drug discrimination, and self-administration in rodents. Data from subjective report assessments in humans following acute dosing of compounds were also included. The predictive value of each model was then evaluated relative to the scheduling status of each drug in the USA. In recognition of the fact that drug scheduling can be influenced by factors other than the pharmacology of the drug, we also evaluated the predictive value of each assay for the outcome of the human subjective effects assessment. This approach provides an objective and statistical assessment of the predictive value of many of the models typically applied within the pharmaceutical industry to evaluate abuse potential risk. In addition, the impact of combining information from multiple models was examined. This analysis adds to our understanding of the predictive value of each model, allows us to critically evaluate the benefits and limitations of each model, and provides a method for identifying opportunities for improving our assessment and prediction of abuse liability risk in the future.

Casein Kinase 1δ/ε Inhibitor PF-5006739 Attenuates Opioid Drug-Seeking Behavior

Casein kinase 1 delta (CK1δ) and casein kinase 1 epsilon (CK1ε) inhibitors are potential therapeutic agents for a range of psychiatric disorders. The feasibility of developing a CNS kinase inhibitor has been limited by an inability to identify safe brain-penetrant compounds with high kinome selectivity. Guided by structure-based drug design, potent and selective CK1δ/ε inhibitors have now been identified that address this gap, through the design and synthesis of novel 4-[4-(4-fluorophenyl)-1-(piperidin-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine derivatives. PF-5006739 (6) possesses a desirable profile, with low nanomolar in vitro potency for CK1δ/ε (IC50 = 3.9 and 17.0 nM, respectively) and high kinome selectivity. In vivo, 6 demonstrated robust centrally mediated circadian rhythm phase-delaying effects in both nocturnal and diurnal animal models. Further, 6 dose-dependently attenuated opioid drug-seeking behavior in a rodent operant reinstatement model in animals trained to self-administer fentanyl. Collectively, our data supports further development of 6 as a promising candidate to test the hypothesis of CK1δ/ε inhibition in treating multiple indications in the clinic.

Pharmacology in translation: the preclinical and early clinical profile of the novel α2/3 functionally selective GABAA receptor positive allosteric modulator PF‐06372865

Benzodiazepines, non‐selective positive allosteric modulators (PAMs) of GABAA receptors, have significant side effects that limit their clinical utility. As many of these side effects are mediated by the α1 subunit, there has been a concerted effort to develop α2/3 subtype‐selective PAMs.

Dopamine D3/D2 Receptor Antagonist PF-4363467 Attenuates Opioid Drug-Seeking Behavior without Concomitant D2 Side Effects

Dopamine receptor antagonism is a compelling molecular target for the treatment of a range of psychiatric disorders, including substance use disorders. From our corporate compound file, we identified a structurally unique D3 receptor (D3R) antagonist scaffold, 1. Through a hybrid approach, we merged key pharmacophore elements from 1 and D3 agonist 2 to yield the novel D3R/D2R antagonist PF-4363467 (3). Compound 3 was designed to possess CNS drug-like properties as defined by its CNS MPO desirability score (≥4/6). In addition to good physicochemical properties, 3 exhibited low nanomolar affinity for the D3R (D3 Ki = 3.1 nM), good subtype selectivity over D2R (D2 Ki = 692 nM), and high selectivity for D3R versus other biogenic amine receptors. In vivo, 3 dose-dependently attenuated opioid self-administration and opioid drug-seeking behavior in a rat operant reinstatement model using animals trained to self-administer fentanyl. Further, traditional extrapyramidal symptoms (EPS), adverse side effects arising from D2R antagonism, were not observed despite high D2 receptor occupancy (RO) in rodents, suggesting that compound 3 has a unique in vivo profile. Collectively, our data support further investigation of dual D3R and D2R antagonists for the treatment of drug addiction.