Predictions of Colloidal Molecular Aggregation Using AI/ML Models.

To facilitate the triage of hits from small molecule screens, we have used various AI/ML techniques and experimentally observed data sets to build models aimed at predicting colloidal aggregation of small organic molecules in aqueous solution. We have found that Naïve Bayesian and deep neural networks outperform logistic regression, recursive partitioning tree, support vector machine, and random forest techniques by having the lowest balanced error rate (BER) for the test set. Derived predictive classification models consistently and successfully discriminated aggregator molecules from nonaggregator hits. An analysis of molecular descriptors in favor of colloidal aggregation confirms previous observations (hydrophobicity, molecular weight, and solubility) in addition to undescribed molecular descriptors such as the fraction of sp3 carbon atoms (Fsp3), and electrotopological state of hydroxyl groups (ES_Sum_sOH). Naïve Bayesian modeling and scaffold tree analysis have revealed chemical features/scaffolds contributing the most to colloidal aggregation and nonaggregation, respectively. These results highlight the importance of scaffolds with high Fsp3 values in promoting nonaggregation. Matched molecular pair analysis (MMPA) has also deciphered context-dependent substitutions, which can be used to design nonaggregator molecules. We found that most matched molecular pairs have a neutral effect on aggregation propensity. We have prospectively applied our predictive models to assist in chemical library triage for optimal plate selection diversity and purchase for high throughput screening (HTS) in drug discovery projects.

Identification of Selective Imidazopyridine CSF1R Inhibitors.

Colony stimulating factor-1 receptor (CSF1R or c-FMS), a class III receptor tyrosine kinase expressed on members of the mononuclear phagocyte system (MPS), plays a key role in the proper functioning of macrophages, microglia, and related cells. Aberrant signaling through CSF1R has been associated with a variety of disease states, including cancer, inflammation, and neurodegeneration. In this Letter, we detail our efforts to develop novel CSF1R inhibitors. Drawing on previously described compounds, including GW2580 (4), we have discovered a novel series of compounds based on the imidazo[4,5-b]pyridine scaffold. Initial structure-activity relationship studies culminated in the identification of 36, a lead compound with potent CSF1R biochemical and cellular activity, acceptable in vitro ADME properties, and oral exposure in rat.

A novel brain-penetrant oral UGT8 inhibitor decreases in vivo galactosphingolipid biosynthesis in murine Krabbe disease.

Krabbe disease is a rare, inherited neurodegenerative disease due to impaired lysosomal ß-galactosylceramidase (GALC) activity and formation of neurotoxic ß-galactosylsphingosine ('psychosine'). We investigated substrate reduction therapy with a novel brain-penetrant inhibitor of galactosylceramide biosynthesis, RA 5557, in twitcher mice that lack GALC activity and model Krabbe disease. This thienopyridine derivative selectively inhibits uridine diphosphate-galactose glycosyltransferase 8 (UGT8), the final step in the generation of galactosylceramides which are precursors of sulphatide and, in the pathological lysosome, the immediate source of psychosine. Administration of RA 5557, reduced pathologically elevated psychosine concentrations (72-86%) in the midbrain and cerebral cortex in twitcher mice: the inhibitor decreased galactosylceramides by about 70% in midbrain and cerebral cortex in mutant and wild type animals. Exposure to the inhibitor significantly decreased several characteristic inflammatory response markers without causing apparent toxicity to myelin-producing cells in wild type and mutant mice; transcript abundance of oligodendrocyte markers MBP (myelin basic protein) and murine UGT8 was unchanged. Administration of the inhibitor before conception and during several breeding cycles to mice did not impair fertility and gave rise to healthy offspring. Nevertheless, given the unchanged lifespan, it appears that GALC has critical functions in the nervous system beyond the hydrolysis of galactosylceramide and galactosylsphingosine. Our findings support further therapeutic exploration of orally active UGT8 inhibitors in Krabbe disease and related galactosphingolipid disorders. The potent thienopyridine derivative with effective target engagement here studied appears to have an acceptable safety profile in vivo; judicious dose optimization will be needed to ensure efficacious clinical translation.

Understanding DP receptor antagonism using a CoMSIA approach.

A Comparative Molecular Similarity Indices Analysis (CoMSIA) was performed for 2,6-substituted-4-monosubstituted aminopyrimidine antagonists of prostaglandin D(2) receptor (DP). Both two-component (Q(2) = 0.63, R(2) = 0.82, SEE = 0.47 pIC(50)) and three-component (Q(2) = 0.70, R(2) = 0.91, SEE = 0.36 pIC(50)) CoMSIA models were established. Two hydrogen-bond acceptors with spatial separation of about 8Å are shown as optimal for binding. A large hydrophobic center that separates the two acceptors confers to the potency of the 2,6-substituted-4-monosubstituted aminopyrimidine. The models were used to predict IC(50) values for compounds which had functional groups different from those in the training set.

Brain Penetrable Inhibitors of Ceramide Galactosyltransferase for the Treatment of Lysosomal Storage Disorders.

Metachromatic leukodystrophy (MLD) is a rare, genetic lysosomal storage disorder caused by the deficiency of arylsulfatase A enzyme, which results in the accumulation of sulfatide in the lysosomes of the tissues of central and peripheral nervous systems, leading to progressive demyelination and neurodegeneration. Currently there is no cure for this disease, and the only approved therapy, hematopoietic stem cell transplant, has limitations. We proposed substrate reduction therapy (SRT) as a novel approach to treat this disease, by inhibiting ceramide galactosyltransferase enzyme (UGT8). This resulted in the identification of a thienopyridine scaffold as a starting point to initiate medicinal chemistry. Further optimization of hit compound 1 resulted in the identification of brain penetrable, orally bioavailable compound 19, which showed efficacy in the in vivo pharmacodynamic models, indicating the potential to treat MLD with UGT8 inhibitors.

Comparing the effects of distilled Rehmannia glutinosa, Wild Ginseng and Astragali Radix pharmacopuncture with heart rate variability (HRV): a randomized, sham-controlled and double-blind clinical trial.

This study compared the effects of distilled Rehmannia glutinosa, Wild Ginseng and Astragali Radix pharmacopuncture on the autonomic nervous system and heart rate variability. The purpose of the trial was to observe the influence distilled Astragali Radix, Wild Ginseng and Rehmannia glutinosa pharmacopuncture have on the autonomic nervous system. 120 healthy male volunteers were divided into four groups, which consisted of three experimental groups and a control group. This study was a randomized, placebo-controlled, double-blind clinical trial. Volunteers in experimental groups were underwent pharmacopuncture at GB21 (Kyonjong), and volunteers in the control group were injected with normal saline at GB21 (Kyonjong). Heart rate variability was measured seven times: before and after injection, every 5 minutes for 30 minutes. The result was distilled Rehmannia glutinosa, Wild Ginseng and Astragali Radix pharmacopuncture in healthy adult males tended to activate the autonomic nervous system, particularly the sympathetic nervous system.

Cardiac ion channel effects of tolterodine.

Tolterodine is a muscarinic antagonist widely used in the treatment of urinary incontinence. Although tolterodine has not been reported to alter cardiac repolarization, it is chemically related to other muscarinic antagonists known to prolong cardiac repolarization. For this reason, we studied the effects of tolterodine on cardiac ion channels and action potential recordings. Using patch-clamp electrophysiology, we found that tolterodine was a potent antagonist of the human ether-a-go-go-related gene (HERG) K(+) channel, displaying an IC(50) value of 17 nM. This potency was similar to that observed for the antiarrhythmic drug dofetilide (IC(50) of 11 nM). Tolterodine block of HERG displayed a positive voltage dependence, suggesting an interaction with an activated state. Tolterodine had little effect on the human cardiac Na(+) channel at concentrations of up to 1 microM. Inhibition of L-type Ca(2+) currents by tolterodine was frequency-dependent with IC(50) values measuring 143 and 1084 nM at 1 and 0.1 Hz, respectively. Both tolterodine and dofetilide prolonged action potential duration in single guinea pig myocytes over the concentration range of 3 to 100 nM. However, prolongation was significantly larger for dofetilide compared with tolterodine. Tolterodine seems to be an unusual drug in that it blocks HERG with high affinity, but produces little QT prolongation clinically. Low plasma levels after therapeutic doses combined with mixed ion channel effects, most notably Ca(2+) channel blockade, may serve to attenuate the QT prolonging effects of this potent HERG channel antagonist.