Discovery and Preclinical Profiling of 3‑[4-(Morpholin-4-yl)‑7<i>H</i>‑pyrrolo[2,3‑<i>d</i>]pyrimidin-5-yl]benzonitrile (PF-06447475), a Highly Potent, Selective, Brain Penetrant, and in Vivo Active LRRK2 Kinase Inhibitor

Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson’s disease (PD) by genome-wide association studies (GWAS). The most common LRRK2 mutation, G2019S, which is relatively rare in the total population, gives rise to increased kinase activity. As such, LRRK2 kinase inhibitors are potentially useful in the treatment of PD. We herein disclose the discovery and optimization of a novel series of potent LRRK2 inhibitors, focusing on improving kinome selectivity using a surrogate crystallography approach. This resulted in the identification of <b>14</b> (PF-06447475), a highly potent, brain penetrant and selective LRRK2 inhibitor which has been further profiled in in vivo safety and pharmacodynamic studies

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, <b>1</b>. Through a hybrid approach, we merged key pharmacophore elements from <b>1</b> and D3 agonist <b>2</b> to yield the novel D3R/D2R antagonist PF-4363467 (<b>3</b>). Compound <b>3</b> was designed to possess CNS drug-like properties as defined by its CNS MPO desirability score (≥4/6). In addition to good physicochemical properties, <b>3</b> exhibited low nanomolar affinity for the D3R (D3 <i>K</i>_i = 3.1 nM), good subtype selectivity over D2R (D2 <i>K</i>_i = 692 nM), and high selectivity for D3R versus other biogenic amine receptors. In vivo, <b>3</b> 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 <b>3</b> has a unique in vivo profile. Collectively, our data support further investigation of dual D3R and D2R antagonists for the treatment of drug addiction

Late-Stage Microsomal Oxidation Reduces Drug–Drug Interaction and Identifies Phosphodiesterase 2A Inhibitor PF-06815189

Late-stage oxidation using liver microsomes was applied to phosphodiesterase 2 inhibitor <b>1</b> to reduce its clearance by cytochrome P450 enzymes, introduce renal clearance, and minimize the risk for victim drug–drug interactions. This approach yielded PF-06815189 (<b>2</b>) with improved physicochemical properties and a mixed metabolic profile. This example highlights the importance of C–H diversification methods to drug discovery

Application of Structure-Based Design and Parallel Chemistry to Identify a Potent, Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor

Phosphodiesterase 2A (PDE2A) inhibitors have been reported to demonstrate in vivo activity in preclinical models of cognition. To more fully explore the biology of PDE2A inhibition, we sought to identify potent PDE2A inhibitors with improved brain penetration as compared to current literature compounds. Applying estimated human dose calculations while simultaneously leveraging synthetically enabled chemistry and structure-based drug design has resulted in a highly potent, selective, brain penetrant compound <b>71</b> (PF-05085727) that effects in vivo biochemical changes commensurate with PDE2A inhibition along with behavioral and electrophysiological reversal of the effects of NMDA antagonists in rodents. This data supports the ability of PDE2A inhibitors to potentiate NMDA signaling and their further development for clinical cognition indications

Identification of a Potent, Highly Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor Clinical Candidate

Computational modeling was used to direct the synthesis of analogs of previously reported phosphodiesterase 2A (PDE2A) inhibitor <b>1</b> with an imidazotriazine core to yield compounds of significantly enhanced potency. The analog PF-05180999 (<b>30</b>) was subsequently identified as a preclinical candidate targeting cognitive impairment associated with schizophrenia. Compound <b>30</b> demonstrated potent binding to PDE2A in brain tissue, dose responsive mouse brain cGMP increases, and reversal of <i>N</i>-methyl-d-aspartate (NMDA) antagonist-induced (MK-801, ketamine) effects in electrophysiology and working memory models in rats. Preclinical pharmacokinetics revealed unbound brain/unbound plasma levels approaching unity and good oral bioavailability resulting in an average concentration at steady state (<i>C</i>_av,ss) predicted human dose of 30 mg once daily (q.d.). Modeling of a modified release formulation suggested that 25 mg twice daily (b.i.d.) could maintain plasma levels of <b>30</b> at or above targeted efficacious plasma levels for 24 h, which became part of the human clinical plan

Application of Structure-Based Design and Parallel Chemistry to Identify a Potent, Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor

Phosphodiesterase 2A (PDE2A) inhibitors have been reported to demonstrate in vivo activity in preclinical models of cognition. To more fully explore the biology of PDE2A inhibition, we sought to identify potent PDE2A inhibitors with improved brain penetration as compared to current literature compounds. Applying estimated human dose calculations while simultaneously leveraging synthetically enabled chemistry and structure-based drug design has resulted in a highly potent, selective, brain penetrant compound <b>71</b> (PF-05085727) that effects in vivo biochemical changes commensurate with PDE2A inhibition along with behavioral and electrophysiological reversal of the effects of NMDA antagonists in rodents. This data supports the ability of PDE2A inhibitors to potentiate NMDA signaling and their further development for clinical cognition indications

Identification of a Potent, Highly Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor Clinical Candidate

Computational modeling was used to direct the synthesis of analogs of previously reported phosphodiesterase 2A (PDE2A) inhibitor <b>1</b> with an imidazotriazine core to yield compounds of significantly enhanced potency. The analog PF-05180999 (<b>30</b>) was subsequently identified as a preclinical candidate targeting cognitive impairment associated with schizophrenia. Compound <b>30</b> demonstrated potent binding to PDE2A in brain tissue, dose responsive mouse brain cGMP increases, and reversal of <i>N</i>-methyl-d-aspartate (NMDA) antagonist-induced (MK-801, ketamine) effects in electrophysiology and working memory models in rats. Preclinical pharmacokinetics revealed unbound brain/unbound plasma levels approaching unity and good oral bioavailability resulting in an average concentration at steady state (<i>C</i>_av,ss) predicted human dose of 30 mg once daily (q.d.). Modeling of a modified release formulation suggested that 25 mg twice daily (b.i.d.) could maintain plasma levels of <b>30</b> at or above targeted efficacious plasma levels for 24 h, which became part of the human clinical plan