Cationic iridium(1) complexes of chiral phosphanodihydrooxazoles were uscd as catalysts for the enantioselective hydrogenation of prochiral N-alkyl and N-aryl imines. The complexes are air-stable crystalline solids that can be readily prepared and are easy to handle. The structures of two complexes were determined by X-ray analysis. For N-alkyl imines of acetophenone, enantiomeric excesses of up to 79% were obtained. Dialkyl ketimines and cyclic imines showed lower reactivity and selectivity. A remarkable dilution effect was observed for the hydrogenation of the N-phenyl imine of acetophenone: decreasing the substrate and catalyst concentration led to a signifi- Keywords

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.

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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.

We recently reported the discovery of a potent, selective, and brainpenetrant 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 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.

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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.