Modulation of Pharmacologically Relevant Properties of Piperidine Derivatives by Functional Groups in an Equatorial or Axial ß-Position to the Amino Group.

Thirteen epimeric pairs of 5-substituted N-piperonyl-3-phenylpiperidine derivatives were synthesized in order to explore the stereospecific modulation of basicity, lipophilicity, aqueous solubility, and membrane permeation by functional groups in equatorial or axial positions beta to the amine unit. While this comprehensive data set provides enhanced insight into multiple factors that affect basicity and lipophilicity, it fills an important knowledge gap, providing a frame of reference for the property-based design of bioactive compounds. Impacts on amine basicity are very pronounced for the ß-equatorial functional groups and parallel basicity-lowering effects known for acyclic amine derivatives. For ß-axial functional groups, the basicity-lowering effects are generally decreased, with the nitrile group as the only exception. Basicity and lipophilicity modulations observed for ß-axial functional groups are quite diverse and rationalized in terms of intramolecular hydrogen bonding, dipolar interactions, and special solvation effects. Aqueous solubility and (artificial) membrane permeability are discussed with reference to lipophilicity.

Perfect Matchings with Crossings.

For sets of n points, n even, in general position in the plane, we consider straight-line drawings of perfect matchings on them. It is well known that such sets admit at least Cn/2 different plane perfect matchings, where Cn/2 is the n/2-th Catalan number. Generalizing this result we are interested in the number of drawings of perfect matchings which have k crossings. We show the following results. (1) For every k≤164n2-3532nn+122564n, any set with n points, n sufficiently large, admits a perfect matching with exactly k crossings. (2) There exist sets of n points where every perfect matching has at most 572n2-n4 crossings. (3) The number of perfect matchings with at most k crossings is superexponential in n if k is superlinear in n. (4) Point sets in convex position minimize the number of perfect matchings with at most k crossings for k=0,1,2, and maximize the number of perfect matchings with n/22 crossings and with n/22-1 crossings.

Selective and brain-penetrant HCN1 inhibitors reveal links between synaptic integration, cortical function, and working memory.

Hyperpolarization-activated and cyclic-nucleotide-gated 1 (HCN1) ion channels are proposed to be critical for cognitive function through regulation of synaptic integration. However, resolving the precise role of HCN1 in neurophysiology and exploiting its therapeutic potential has been hampered by minimally selective antagonists with poor potency and limited in vivo efficiency. Using automated electrophysiology in a small-molecule library screen and chemical optimization, we identified a primary carboxamide series of potent and selective HCN1 inhibitors with a distinct mode of action. In cognition-relevant brain circuits, selective inhibition of native HCN1 produced on-target effects, including enhanced excitatory postsynaptic potential summation, while administration of a selective HCN1 inhibitor to rats recovered decrement working memory. Unlike prior non-selective HCN antagonists, selective HCN1 inhibition did not alter cardiac physiology in human atrial cardiomyocytes or in rats. Collectively, selective HCN1 inhibitors described herein unmask HCN1 as a potential target for the treatment of cognitive dysfunction in brain disorders.

Selective oxytocin receptor activation prevents prefrontal circuit dysfunction and social behavioral alterations in response to chronic prefrontal cortex activation in male rats.

Introduction: Social behavioral changes are a hallmark of several neurodevelopmental and neuropsychiatric conditions, nevertheless the underlying neural substrates of such dysfunction remain poorly understood. Building evidence points to the prefrontal cortex (PFC) as one of the key brain regions that orchestrates social behavior. We used this concept with the aim to develop a translational rat model of social-circuit dysfunction, the chronic PFC activation model (CPA). Methods: Chemogenetic designer receptor hM3Dq was used to induce chronic activation of the PFC over 10 days, and the behavioral and electrophysiological signatures of prolonged PFC hyperactivity were evaluated. To test the sensitivity of this model to pharmacological interventions on longer timescales, and validate its translational potential, the rats were treated with our novel highly selective oxytocin receptor (OXTR) agonist RO6958375, which is not activating the related vasopressin V1a receptor. Results: CPA rats showed reduced sociability in the three-chamber sociability test, and a concomitant decrease in neuronal excitability and synaptic transmission within the PFC as measured by electrophysiological recordings in acute slice preparation. Sub-chronic treatment with a low dose of the novel OXTR agonist following CPA interferes with the emergence of PFC circuit dysfunction, abnormal social behavior and specific transcriptomic changes. Discussion: These results demonstrate that sustained PFC hyperactivity modifies circuit characteristics and social behaviors in ways that can be modulated by selective OXTR activation and that this model may be used to understand the circuit recruitment of prosocial therapies in drug discovery.

Arrangements of Approaching Pseudo-Lines.

We consider arrangements of n pseudo-lines in the Euclidean plane where each pseudo-line ℓ i is represented by a bi-infinite connected x-monotone curve f i ( x ) , x ∈ R , such that for any two pseudo-lines ℓ i and ℓ j with i < j , the function x ↦ f j ( x ) - f i ( x ) is monotonically decreasing and surjective (i.e., the pseudo-lines approach each other until they cross, and then move away from each other). We show that such arrangements of approaching pseudo-lines, under some aspects, behave similar to arrangements of lines, while for other aspects, they share the freedom of general pseudo-line arrangements. For the former, we prove:There are arrangements of pseudo-lines that are not realizable with approaching pseudo-lines.Every arrangement of approaching pseudo-lines has a dual generalized configuration of points with an underlying arrangement of approaching pseudo-lines. For the latter, we show:There are 2 Θ ( n 2 ) isomorphism classes of arrangements of approaching pseudo-lines (while there are only 2 Θ ( n log n ) isomorphism classes of line arrangements).It can be decided in polynomial time whether an allowable sequence is realizable by an arrangement of approaching pseudo-lines. Furthermore, arrangements of approaching pseudo-lines can be transformed into each other by flipping triangular cells, i.e., they have a connected flip graph, and every bichromatic arrangement of this type contains a bichromatic triangular cell.

Discovery of potent, balanced and orally active dual NK1/NK3 receptor ligands.

During a program directed at selective NK(1) receptor antagonists, we serendipitously discovered an NK(1) receptor ligand with additional affinity for the NK(3) receptor. Recognising an opportunity for a drug discovery program aiming for dual NK(1)/NK(3) receptor antagonists, we prepared a series of analogues from a novel, versatile building block. From this series emerged compounds with high and balanced affinities for the NK(1) and the NK(3) receptors. Typical representatives of this series were active in the gerbil foot tapping assay after oral administration.

Discovery of Balovaptan, a Vasopressin 1a Receptor Antagonist for the Treatment of Autism Spectrum Disorder.

We recently reported the discovery of a potent, selective, and brain-penetrant V1a receptor antagonist, which was not suitable for full development. Nevertheless, this compound was found to improve surrogates of social behavior in adults with autism spectrum disorder in an exploratory proof-of-mechanism study. Here we describe scaffold hopping that gave rise to triazolobenzodiazepines with improved pharmacokinetic properties. The key to balancing potency and selectivity while minimizing P-gp mediated efflux was fine-tuning of hydrogen bond acceptor basicity. Ascertaining a V1a antagonist specific brain activity pattern by pharmacological magnetic resonance imaging in the rat played a seminal role in guiding optimization efforts, culminating in the discovery of balovaptan (RG7314, RO5285119) 1. In a 12-week clinical phase 2 study in adults with autism spectrum disorder balovaptan demonstrated improvements in Vineland-II Adaptive Behavior Scales, a secondary end point comprising communication, socialization, and daily living skills. Balovaptan entered phase 3 clinical development in August 2018.

From receptor binding kinetics to signal transduction; a missing link in predicting in vivo drug-action.

An important question in drug discovery is how to overcome the significant challenge of high drug attrition rates due to lack of efficacy and safety. A missing link in the understanding of determinants for drug efficacy is the relation between drug-target binding kinetics and signal transduction, particularly in the physiological context of (multiple) endogenous ligands. We hypothesized that the kinetic binding parameters of both drug and endogenous ligand play a crucial role in determining cellular responses, using the NK1 receptor as a model system. We demonstrated that the binding kinetics of both antagonists (DFA and aprepitant) and endogenous agonists (NKA and SP) have significantly different effects on signal transduction profiles, i.e. potency values, in vitro efficacy values and onset rate of signal transduction. The antagonistic effects were most efficacious with slowly dissociating aprepitant and slowly associating NKA while the combination of rapidly dissociating DFA and rapidly associating SP had less significant effects on the signal transduction profiles. These results were consistent throughout different kinetic assays and cellular backgrounds. We conclude that knowledge of the relationship between in vitro drug-target binding kinetics and cellular responses is important to ultimately improve the understanding of drug efficacy in vivo.

Discovery of highly selective brain-penetrant vasopressin 1a antagonists for the potential treatment of autism via a chemogenomic and scaffold hopping approach.

From a micromolar high throughput screening hit 7, the successful complementary application of a chemogenomic approach and of a scaffold hopping exercise rapidly led to a low single digit nanomolar human vasopressin 1a (hV1a) receptor antagonist 38. Initial optimization of the mouse V1a activities delivered suitable tool compounds which demonstrated a V1a mediated central in vivo effect. This novel series was further optimized through parallel synthesis with a focus on balancing lipophilicity to achieve robust aqueous solubility while avoiding P-gp mediated efflux. These efforts led to the discovery of the highly potent and selective brain-penetrant hV1a antagonist RO5028442 (8) suitable for human clinical studies in people with autism.

Greatly Simplified Procedures for the Synthesis of alpha-Amino Acids by the Direct Alkylation of Pseudoephedrine Glycinamide Hydrate.

A modified procedure for the synthesis of highly enantiomerically enriched alpha-amino acids is described that involves the direct alkylation of pseudoephedrine glycinamide hydrate (1.H(2)O) followed by hydrolysis. The modified procedure was developed to overcome several inconvenient aspects of our earlier reported procedure. Advantages of the new method include (1) a greatly simplified one-step synthesis of the alkylation substrate (1.H(2)O) by the direct combination of glycine methyl ester hydrochloride with pseudoephedrine in the presence of lithium tert-butoxide, (2) the use of the weaker base lithium hexamethyldisilazide (LHMDS) in lieu of lithium diisopropylamide (LDA) for the enolization reaction, (3) a protocol for the direct alkylation of 1.H(2)O without the need for prior drying of the alkylation substrate, and (4) a one-step alkylation procedure that generates LHMDS and anhydrous lithium chloride simultaneously from the reaction of lithium metal with n-hexyl chloride in the presence of hexamethyldisilazane.

Enantioselective Hydrogenation of Olefins with Iridium-Phosphanodihydrooxazole Catalysts.

High turnover numbers and up to 98% ee were obtained in the catalytic hydrogenation of unfunctionalized aryl-substituted olefins with iridium-phosphanyldihydrooxazole complexes 1 (see reaction scheme). The anion of the complex-for example, hexafluorophosphate or tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (BARF- )-has a remarkable effect on the reactivity and longevity of the catalyst.

Identification of a crucial amino acid in the helix position 6.51 of human tachykinin neurokinin 1 and 3 receptors contributing to the insurmountable mode of antagonism by dual NK1/NK3 antagonists.

The neurokinins are neuropeptides that elicit their effect through three GPCRs called NK(1), NK(2), and NK(3). Compounds 5 and 6 are dual hNK(1) (K(i) of 0.7 and 0.3 nM) and hNK(3) (K(i) of 2.9 and 1.7 nM) antagonists. Both compounds exhibit an insurmountable mode of antagonism at hNK(1), whereas at hNK(3), they differ in that 5 is an insurmountable but 6 a surmountable antagonist. Using homology modeling and site-directed mutagenesis, hNK(1)-Phe264 and hNK(3)-Tyr315 were found to be the molecular determinants of hNK(1) and hNK(3) antagonism by 5 and 6. In [(3)H]IP studies, the mutation hNK(1)-F264Y converted the mode of action of 5 from insurmountable to partial insurmountable antagonism while it had no effect on that of 6. Conversely, the mutation hNK(3)-Y315F enhanced the insurmountable behavior of 5 and converted 6's surmountable to an insurmountable antagonism. This finding was further confirmed by characterizing additional derivatives of 5 and 6, most notably with a hybrid structure.

ROCK: the Roche medicinal chemistry knowledge application - design, use and impact.

Medicinal chemistry is a complex science that lies at the interface of many fields of research and at the very heart of drug discovery, with property relationships based on chemical structure at its core. It is clear that the effective capture and dissemination of medicinal chemistry knowledge and experience will be a key differentiator among pharmaceutical organizations and crucial for the future success in delivering effective and safe drug candidates. Therefore, in 2005 we developed ROCK (Roche medicinal chemistry knowledge), an internal user-friendly and peer-reviewed Wiki-like application to capture, browse and search tacit knowledge, key discoveries and property effects related to chemical structure, which is used as a primary source for addressing challenges faced in drug design.

Pharmacological promiscuity: dependence on compound properties and target specificity in a set of recent Roche compounds.

The term "pharmacological promiscuity" describes a compound's pharmacological activity at multiple targets. Pharmacological promiscuity is undesired in typical drug discovery projects, which focus on the "one drug-one target" paradigm. Off-target activity can lead to adverse drug reactions, or can obscure pharmacodynamic effects in animal models. Therefore, advanced lead compounds, pharmacological tool compounds, and drug candidates are usually screened against panels of safety-relevant targets to detect unwanted pharmacological activities. To identify determinants of pharmacological promiscuity, we compared the panel screening outcomes of 213 recent Roche compounds with their molecular properties. Pronounced promiscuity was not observed below a threshold Clog P value of 2. For basic compounds, the propensity for weak off-target activity was found to increase with calculated basicities, whereas the potential for strong off-target activity depends more qualitatively on the presence of a positive charge at physiological pH. Compounds originating from projects with an aminergic receptor or transporter as a therapeutic target are particularly prone to promiscuity; the promiscuity of such compounds is mainly caused by their activity at other aminergic targets in the screening panel.

The importance of width/length ratios of maxillary anterior permanent teeth in esthetic rehabilitation.

The aim of this study was to investigate the importance of the width/length (W/L) ratio of maxillary anterior permanent teeth in anterior esthetic rehabilitation. Digital photographs were taken of the anterior teeth for each participant (approximately 20 years old). A maxillary impression was taken with irreversible hydrocolloid and cast in die stone under vacuum. The widest mesiodistal width and incisogingival length of the tested teeth were measured. The data were submitted to analysis of variance, which showed significant statistical differences within each parameter (P< .05). The width and length measurements varied between maxillary anterior teeth in the following or der: central incisors > canines > lateral incisors. Maxillary central incisors displayed the largest W/L ratio (85%), maxillary lateral incisors (LI) displayed the smallest W/L ratio (79%), and canines displayed the intermediate W/L ratio (83%). These dimensions have a positive effect on the final restoration; therefore, it is suggested that the specific width, length, and W/L ratio should be used in esthetic rehabilitations of maxillary anterior teeth.

Design and synthesis of a novel, achiral class of highly potent and selective, orally active neurokinin-1 receptor antagonists.

The discovery of a novel, achiral pyridine class of potent and orally active neurokinin-1 (NK(1)) receptor antagonists is described. The evaluation of this class is briefly outlined, leading to the identification of netupitant 21 and befetupitant 29, two new proprietary chemical entities with high affinity and excellent CNS penetration.