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.

Alzheimer's disease (AD) is the most common dementia in elderly. It is characterized by progressive memory loss accompanied by declining activities of daily living and neuropsychiatric symptoms and behavioral changes. In the brains of AD patients extracellular senile plaques composed of Aß peptides, intracellular neurofibrillary tangles consisting mainly of hyperphosphorylated tau and prominent neuronal loss are observed. Inhibition of g -secretase, the Aß-producing enzyme, is therapeutically unfavorable since it leads to Notch-related (another substrate of g -sercetase) toxicity in the thymus, gut and spleen. g -secretase modulators do not inhibit the enzyme but shift the formation of the toxic Aß42 peptide mainly to the formation of non-toxic Aß38 peptide without interfering with the processing of Notch. In the course of the optimization of the g -secretase modulators we tested the compounds in vitro in H4 cells overexpressing Aß42 and in vivo in an APP-transgenic mouse model as well as in non-transgenic rats for specific reduction of A b 42 in brain or CSF. Starting from a previously reported g -secretase modulator 1 with an aminopyrimidine core we exchanged the central core by an aminotriazolopyridine core leading to highly potent compound 2 in vitro (IC 50 = 92 nM). Replacement of the typical aromatic headgroup by a novel saturated aminopiperidine headgroup led to compound 3 with improved physicochemical properties and excellent brain activity in the transgenic mouse model as well as significant reduction of Aß42 in CSF of non-transgenic rats. A novel headgroup for g -secretase modulators was designed which provided compounds with excellent in vivo activity. We will describe detailed SAR and molecular properties for key compounds in this novel class.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

The DNA gyrase inhibitor cyclothialidine had been shown to be a valuable lead structure for the discovery of new antibacterial classes able to overcome bacterial resistance to clinically used drugs. Bicyclic lactone derivatives containing in their 12-14-membered ring a thioamide functionality were reported previously to exhibit potent antibacterial activity against gram-positive bacteria. Moderate in vivo efficacy, however, was demonstrated only for derivatives bearing hydrophilic substituents, which were found to have a favorable impact on pharmcokinetics, and to reduce metabolic degradation, in particular glucuronidation. The incorporation of an additional amide unit into the 14-membered monolactam-lactone scaffold of cyclothialidine analogues provided a new "dilactam" subclass of DNA gyrase inhibitors of inherently higher polarity. After adjusting their lipophilicity by methyl-halogen exchange at the benzene ring, compounds of this series did not require the thioamide functionality to exert a decent antibacterial potency and consequently exhibited improved pharmacokinetic properties resulting in a pronounced in vivo efficacy in a mouse septicaemia infection model.

Alzheimer's disease (AD) is the most common dementia in elderly. It is characterized by progressive memory loss together with declining activities of daily living and neuropsychiatric symptoms or behavioral changes. In the brain of AD patients extracellular senile plaques composed of ß-amyloid (Aß) peptides, intracellular neurofibrillary tangles consisting mainly of hyperphosphorylated tau proteins and neuronal loss is observed. Gene mutations identified in patients with familial AD result in changes in the production of Ab peptides leading to amyloidosis. Aß is released after the consecutive cleavage of amyloid precursor protein (APP) by the two aspartic proteases ß- and -secretase. Therefore -secretase is an attractive target for developing AD drugs. However, inhibition of -secretase also leads to notch related toxicity in the thymus, gut and spleen. To circumvent this liability we screened for compounds which do not inhibit but modulate -secretase activity by shifting the formation of the toxic Aß42 peptide mainly to the formation of the shorter non-toxic Aß fragments. Compound 1 was found as an HTS hit with potent selective -secretase modulatory activity (IC50(Aß42) = 800 nM). In the course of optimization the oxadiazole head group of the screening hit was replaced by an imidazole and the aminothiazole core by an amino pyrimidine leading to compounds 2 and 3 with increased potency (IC50 = 100 nM and 180 nM respectively). These compounds also demonstrate brain activity in a transgenic mouse model for AD as well as significant activity on Ab42 in CSF of non-transgenic rats. We will show compound properties and detailed SAR. Based on the in vivo data and physicochemical properties we performed PK/PD modeling for prediction of human doses.

A compound of the general formula: R1 is -C (O) -lower, cyano or is hetaryl O-alkyl; hetaryl is a heteroaryl group of five or six membered ring optionally substituted with R '; R 'is halogen, C1-C7 alkyl, C1-C7 alkyl substituted by halogen, C1-C7 or C1-C7 substituted by halogen; R2 is hydrogen, C1-C7 alkoxy, C1-C7, halogen or cyano; R3 is - (CH2) nC (O) O-C1-C7, C1-C7, C1-C7 alkoxy, hydroxy, -O-Si (CH3) 2-C1-C7, -C (O) -N (C1-C7) 2, -OS (O) 2-C1-C7, C3-7 cycloalkyl, S (O) 2-aryl, heterocyclyl, -C (O) -heterocyclyl, or is aryl or hetaryl, which aryl or hetaryl rings are optionally substituted by one or more R ''; R4 is hydrogen, C1-C7, hydroxy or CH2CN; X is S or -N = C (R5) -; R5 is hydrogen, C1-C7 alkyl or hydroxy, Y is a bond, -O-, -CH2-, -CH2-CH2-, OO or -N (R) -; R is hydrogen, C1-C7, C (O) O-C1-C7, C (O) -C1-C7, S (O) 2-C1-C7 or benzyl; n is 0 or 1; or their addition salts with pharmaceutically acceptable acid.

A series of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives was evaluated as non-competitive mGluR2/3 antagonists. Replacement of the (2-aryl)-ethynyl-moiety in 8-position with smaller less lipophilic substituents produced compounds inhibiting the binding of [3H]-LY354740 to rat mGluR2 with low nanomolar affinity and consistent functional effect at both mGluR2 and mGluR3. These compounds were able to reverse LY354740-mediated inhibition of field excitatory postsynaptic potentials in the rat dentate gyrus and in vivo activity could be demonstrated by reversal of the LY354740-induced hypoactivity in mice after oral administration.