Direct Comparison of the Prediction of the Unbound Brain-to-Plasma Partitioning Utilizing Machine Learning Approach and Mechanistic Neuropharmacokinetic Model.

The mechanistic neuropharmacokinetic (neuroPK) model was established to predict unbound brain-to-plasma partitioning (Kp,uu,brain) by considering in vitro efflux activities of multiple drug resistance 1 (MDR1) and breast cancer resistance protein (BCRP). Herein, we directly compare this model to a computational machine learning approach utilizing physicochemical descriptors and efflux ratios of MDR1 and BCRP-expressing cells for predicting Kp,uu,brain in rats. Two different types of machine learning techniques, Gaussian processes (GP) and random forest regression (RF), were assessed by the time and cluster-split validation methods using 640 internal compounds. The predictivity of machine learning models based on only molecular descriptors in the time-split dataset performed worse than the cluster-split dataset, whereas the models incorporating MDR1 and BCRP efflux ratios showed similar predictivity between time and cluster-split datasets. The GP incorporating MDR1 and BCRP in the time-split dataset achieved the highest correlation (R2 = 0.602). These results suggested that incorporation of MDR1 and BCRP in machine learning is beneficial for robust and accurate prediction. Kp,uu,brain prediction utilizing the neuroPK model was significantly worse compared to machine learning approaches for the same dataset. We also investigated the predictivity of Kp,uu,brain using an external independent test set of 34 marketed drugs. Compared to machine learning models, the neuroPK model showed better predictive performance with R2 of 0.577. This work demonstrates that the machine learning model for Kp,uu,brain achieves maximum predictive performance within the chemical applicability domain, whereas the neuroPK model is applicable more widely beyond the chemical space covered in the training dataset.

Discovery of {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol, systemically potent novel non-peptide agonist of nociceptin/orphanin FQ receptor as analgesic for the treatment of neuropathic pain: design, synthesis, and structure-activity relationships.

Neuropathic pain is a serious chronic disorder caused by lesion or dysfunction in the nervous systems. Endogenous nociceptin/orphanin FQ (N/OFQ) peptide and N/OFQ peptide (NOP) receptor [or opioid-receptor-like-1 (ORL1) receptor] are located in the central and peripheral nervous systems, the immune systems, and peripheral organs, and have a crucial role in the pain sensory system. Indeed, peripheral or intrathecal N/OFQ has displayed antinociceptive activities in neuropathic pain models, and inhibitory effects on pain-related neurotransmitter releases and on synaptic transmissions of C- and Aδ-fibers. In this study, design, synthesis, and structure-activity relationships of peripheral/spinal cord-targeting non-peptide NOP receptor agonist were investigated for the treatment of neuropathic pain, which resulted in the discovery of highly selective and potent novel NOP receptor full agonist {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol 1 (HPCOM) as systemically (subcutaneously) potent new-class analgesic. Thus, 1 demonstrates dose-dependent inhibitory effect against mechanical allodynia in chronic constriction injury-induced neuropathic pain model rats, robust metabolic stability and little hERG potassium ion channel binding affinity, with its unique and potentially safe profiles and mechanisms, which were distinctive from those of N/OFQ in terms of site-differential effects.

Discovery of 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole: integrated drug-design and structure-activity relationships for orally potent, metabolically stable and potential-risk reduced novel non-peptide nociceptin/orphanin FQ receptor agonist as antianxiety drug.

Anxiety disorders, caused by continuous or acute stress or fear, have been highly prevailing psychiatric disorders. For the acute treatment of the disorders, benzodiazepines have been widely used despite having liabilities that limit their utility. Alternatively, endogenous nociceptin/orphanin FQ and nociceptin/orphanin FQ peptide receptor (or opioid-receptor-like-1 receptor) have important roles in the integration of emotional components, e.g. anxiolytic activity is the key behavioral action of nociceptin/orphanin FQ in brain. In our preceding study, various structurally novel 1,2-disubstituted benzimidazole derivatives were designed and synthesized as highly potent nociceptin/orphanin FQ peptide receptor selective full agonists in vitro with high or moderate nociceptin/orphanin FQ peptide receptor occupancy in the mice brain per os based on appropriate physicochemical properties for the oral brain activity [Hayashi et al. (2009) J Med Chem;52:610-625]. In the present study, drug design and structure-activity relationships for Vogel anticonflict activities in mice per os, metabolic stabilities in human liver microsome, CYP2D6 inhibitions, serum protein bindings, and human ether-a-go-go related gene binding affinities of novel nociceptin/orphanin FQ peptide receptor agonists were investigated. Through the series of coherent drug discovery studies, the strongest nociceptin/orphanin FQ peptide receptor agonist, 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole was designed and identified as a new-class orally potent anxiolytic with little side-effects, as significant findings.

Structure-activity relationship study of novel NR2B-selective antagonists with arylamides to avoid reactive metabolites formation.

A novel potent NMDA-NR2B selective antagonist without the reactive metabolites formation issue was identified. Through this study, a close correlation between reactive metabolites formation and calculated HOMO energies of parent compounds was found.