Keranen H.,Janssen Pharmaceutical |
Perez-Benito L.,Autonomous University of Barcelona |
Ciordia M.,Neuroscience Medicinal Chemistry |
Delgado F.,Neuroscience Medicinal Chemistry |
And 5 more authors.
Journal of Chemical Theory and Computation | Year: 2017
A series of acylguanidine beta secretase 1 (BACE1) inhibitors with modified scaffold and P3 pocket substituent was synthesized and studied with free energy perturbation (FEP) calculations. The resulting molecules showed potencies in enzymatic BACE1 inhibition assays up to 1 nM. The correlation between the predicted activity from the FEP calculations and the experimental activity was good for the P3 pocket substituents. The average mean unsigned error (MUE) between prediction and experiment was 0.68 ± 0.17 kcal/mol for the default 5 ns lambda window simulation time improving to 0.35 ± 0.13 kcal/mol for 40 ns. FEP calculations for the P2′ pocket substituents on the same acylguanidine scaffold also showed good agreement with experiment and the results remained stable with repeated simulations and increased simulation time. It proved more difficult to use FEP calculations to study the scaffold modification from increasing 5 to 6 and 7 membered-rings. Although prediction and experiment were in agreement for short 2 ns simulations, as the simulation time increased the results diverged. This was improved by the use of a newly developed "Core Hopping FEP+" approach, which also showed improved stability in repeat calculations. The origins of these differences along with the value of repeat and longer simulation times are discussed. This work provides a further example of the use of FEP as a computational tool for molecular design. © 2017 American Chemical Society.
Oehlrich D.,Neuroscience Medicinal Chemistry |
Prokopcova H.,Neuroscience Medicinal Chemistry |
Gijsen H.J.M.,Neuroscience Medicinal Chemistry
Bioorganic and Medicinal Chemistry Letters | Year: 2014
Beta site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors hold great potential as disease modifying anti-Alzheimer's drugs. This digest provides an overview of the amidine containing class of BACE1 inhibitors, of which multiple examples are now progressing through clinical trials. The various structural modifications highlight the struggle to combine potency with the optimal properties for a brain penetrant BACE1 inhibitor, and illustrate the crowded competitive landscape. This overview concludes with a summary of potential issues including substrate and target selectivity and a synopsis of the status of the current and past clinical assets. © 2014 Elsevier Ltd. All rights reserved.
Bartolome-Nebreda J.M.,Neuroscience Medicinal Chemistry |
Delgado F.,Neuroscience Medicinal Chemistry |
Martin-Martin M.L.,Neuroscience Medicinal Chemistry |
Martinez-Viturro C.M.,Neuroscience Medicinal Chemistry |
And 10 more authors.
Journal of Medicinal Chemistry | Year: 2014
We report the discovery of a series of imidazo[1,2-a]pyrazine derivatives as novel inhibitors of phosphodiesterase 10A (PDE10A). In a high-throughput screening campaign we identified the imidazopyrazine derivative 1, a PDE10A inhibitor with limited selectivity versus the other phosphodiesterases (PDEs). Subsequent investigation of 1 and replacement of the trimethoxyphenyl group by a (methoxyethyl)pyrazole moiety maintained PDE10A inhibition but enhanced selectivity against the other PDEs. Systematic examination and analysis of structure-activity and structure-property relationships resulted in the discovery of 2, an in vitro potent and selective inhibitor of PDE10A with high striatal occupancy of PDE10A, promising in vivo efficacy in different rodent behavioral models of schizophrenia, and a good pharmacokinetic profile in rats. © 2014 American Chemical Society.
Van Brandt S.,Neuroscience Medicinal Chemistry |
Rombouts F.J.R.,Neuroscience Medicinal Chemistry |
Martinez-Lamenca C.,Neuroscience Medicinal Chemistry |
Leenaerts J.,Neuroscience Medicinal Chemistry |
And 2 more authors.
European Journal of Organic Chemistry | Year: 2012
A simple and scalable procedure to introduce alcohols selectively at the 3-position of 3,4,5-trifluoroaniline is described. The procedure uses powdered NaOH as base and catalytic 15-crown-5 in refluxing toluene with a Dean-Stark trap. A short exploration of other nucleophiles and fluoroaryl electrophiles is also described. © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Tresadern G.,Janssen Pharmaceutical |
Cid J.-M.,Neuroscience Medicinal Chemistry |
Trabanco A.A.,Neuroscience Medicinal Chemistry
Journal of Molecular Graphics and Modelling | Year: 2014
Two QSAR approaches were applied to assist the design and to prioritise the synthesis of new active mGlu2 receptor positive allosteric modulators (PAMs). With the aim to explore a particular point of substitution the models successfully prioritised molecules originating from chemistry ideas and a large virtual library. The two methods, 3D topomer CoMFA and support vector machines with 2D ECFP6 fingerprints, delivered good correlation and success in this prospective application. Fourteen molecules with different substituent decoration were identified by the in silico models and synthesised. They were found to be highly active and their mGlu2 receptor PAM activity (pEC 50) was predicted within 0.3 and 0.4 log units of error with the two methods. The value of the molecules and the models for the future of the project is discussed. © 2014 Elsevier Inc.
Wager T.T.,Neuroscience Medicinal Chemistry |
Wager T.T.,Pfizer |
Chandrasekaran R.Y.,Neuroscience Medicinal Chemistry |
Hou X.,Neuroscience Medicinal Chemistry |
And 4 more authors.
ACS Chemical Neuroscience | Year: 2010
As part of our effort to increase survival of drug candidates and to move our medicinal chemistry design to higher probability space for success in the Neuroscience therapeutic area, we embarked on a detailed study of the property space for a collection of central nervous system (CNS) molecules. We carried out a thorough analysis of properties for 119 marketed CNS drugs and a set of 108 Pfizer CNS candidates. In particular, we focused on understanding the relationships between physicochemical properties, in vitro ADME (absorption, distribution, metabolism, and elimination) attributes, primary pharmacology binding efficiencies, and in vitro safety data for these two sets of compounds. This scholarship provides guidance for the design of CNS molecules in a property space with increased probability of success and may lead to the identification of druglike candidates with favorable safety profiles that can successfully test hypotheses in the clinic. © 2010 American Chemical Society.
Jimenez-Aquino A.,Neuroscience Medicinal Chemistry |
Jimenez-Aquino A.,University of Oviedo |
Vega J.A.,Neuroscience Medicinal Chemistry |
Trabanco A.A.,Neuroscience Medicinal Chemistry |
Valdes C.,University of Oviedo
Advanced Synthesis and Catalysis | Year: 2014
1,1,1-Trifluoroacetone tosylhydrazone is presented as a very convenient substrate for the palladium-catalyzed cross-coupling with aryl halides. Under the proper reaction conditions, 3,3,3-trifluoromethylstyrenes - very valuable trifluoromethylated synthetic intermediates - are obtained with high yields. The reaction features a very wide scope, as the presence of most functional groups is tolerated. Moreover, the reaction has been extended to substituted trifluoromethylstyrenes by employing substituted tosylhydrazones derived from other trifluoromethyl ketones. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Pollard M.,Janssen Pharmaceutical |
Bartolome J.M.,Neuroscience Medicinal Chemistry |
Conn P.J.,Vanderbilt University |
Steckler T.,Janssen Pharmaceutical |
Shaban H.,Janssen Pharmaceutical
Journal of Psychopharmacology | Year: 2014
Suppressing anxiety and fear memory relies on bidirectional projections between the medial prefrontal cortex and the amygdala. Positive allosteric modulators of mGluR5 improve cognition in animal models of schizophrenia and retrieval of newly formed associations such as extinction of fearconditioned behaviour. The increase in neuronal network activities of the medial prefrontal cortex is influenced by both mGluR1 and mGluR5; however, it is not well understood how they modulate network activities and downstream information processing. To map mGluR5-mediated network activity in relation to its emergence as a viable cognitive enhancer, we tested group I mGluR compounds on medial prefrontal cortex network activity via multielectrode array neuronal spiking and whole-cell patch clamp recordings. Results indicate that mGluR5 activation promotes feed-forward inhibition that depends on recruitment of neuronal activity by carbachol-evoked up states. The rate of neuronal spiking activity under the influence of carbachol was reduced by the mGluR5 positive allosteric modulator, N-(1,3-Diphenyl-1H-pyrazolo-5-yl)-4-nitrobenzamide (VU-29), and enhanced by the mGluR5 negative allosteric modulator, 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride (MTEP). Spontaneous inhibitory post-synaptic currents were increased upon application of carbachol and in combination with VU-29. These results emphasize a bias towards tonic mGluR5-mediated inhibition that might serve as a signal-to-noise enhancer of sensory inputs projected from associated limbic areas onto the medial prefrontal cortex neuronal microcircuit. © The Author(s) 2014.
Rook J.M.,Vanderbilt University |
Xiang Z.,Vanderbilt University |
Lv X.,Vanderbilt University |
Ghoshal A.,Vanderbilt University |
And 23 more authors.
Neuron | Year: 2015
Schizophrenia is associated with disruptions in N-methyl-D-aspartate glutamate receptor subtype (NMDAR)-mediated excitatory synaptic signaling. The metabotropic glutamate receptor subtype 5 (mGlu5) is a closely associated signaling partner with NMDARs and regulates NMDAR function in forebrain regions implicated in the pathology of schizophrenia. Efficacy of mGlu5 positive allosteric modulators (PAMs) in animal models of psychosis and cognition was previously attributed to potentiation of NMDAR function. To directly test this hypothesis, we identified VU0409551 as a novel mGlu5 PAMthat exhibits distinct stimulus bias and selectively potentiates mGlu5 coupling to Gαq-mediated signaling but not mGlu5 modulation of NMDAR currents or NMDAR-dependent synaptic plasticity in the rat hippocampus. Interestingly, VU0409551 produced robust antipsychotic-like and cognition-enhancing activity in animal models. These data provide surprising new mechanistic insights into the actions of mGlu5 PAMs and suggest that modulation of NMDAR currents is not critical for invivo efficacy. © 2015 Elsevier Inc.
PubMed | Discovery science ADME Tox, Vanderbilt University and Neuroscience Medicinal Chemistry
Type: Journal Article | Journal: Bioorganic & medicinal chemistry letters | Year: 2016
As part of our efforts to identify a suitable back-up compound to our recently disclosed mGlu5 positive allosteric modulator (PAM) clinical candidate VU0490551/JNJ-46778212, this letter details the investigation and challenges of a novel series of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives. From these efforts, compound 4k emerged as a potent and selective mGlu5 PAM displaying overall attractive in vitro (pharmacological and ADMET) and PK profiles combined with in vivo efficacy in preclinical models of schizophrenia. However, further advancement of the compound was precluded due to severely limiting CNS-related side-effects confirming the previously reported association between excessive mGlu5 activation and target-related toxicities.