Literature Search Results for Gene DMPK

1Bioorg. Med. Chem. Lett. 2011 Mar 21: 1896-9
PMID21320776
TitleSynthesis and SAR of sulfoxide substituted carboxyquinolines as NK3 receptor antagonists.
AbstractThe neurokinin-3 (NK3) receptor is regarded as a potential novel target for treating patients with schizophrenia. Herein we report the synthesis and SAR of a series of C3-alkylsulfoxide substituted quinolines as potent NK3 receptor antagonists. These compounds have excellent NK3 functional activity, good selectivity and drug-like properties. Several key compounds have good in vitro/in vivo DMPK characteristics, and are active in a gerbil locomotor activity model.
SCZ Keywordsschizophrenia
2ACS Chem Neurosci 2011 Aug 2: 450-70
PMID22860171
TitleProgress toward positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5).
AbstractThis Review describes recent trends in the development of small molecule mGlu(5) positive allosteric modulators (PAMs). A large body of pharmacological, genetic, electrophysiological, and in vivo behavioral evidence has accumulated over the past decade which continues to support the hypothesis and rationale for the activation of the metabotropic glutamate receptor subtype 5 (mGlu(5)) as a viable and promising target for the development of novel antipsychotics. Until recently, functionally efficacious and potent mGlu(5) PAMs have been somewhat structurally limited in scope and slow to emerge. This Review will discuss efforts since late 2008 which have provided novel mGlu(5) PAM chemotypes, offering ligands with a diverse range of pharmacological, physicochemical, and DMPK properties that were previously unavailable. In addition, significant biological studies of importance in the past few years using the well established PAMs known as DFB, CPPHA, CDPPB, and ADX-47273 will be discussed.
SCZ Keywordsschizophrenia
3ACS Chem Neurosci 2012 Nov 3: 884-95
PMID23173069
TitleTargeting selective activation of M(1) for the treatment of Alzheimer's disease: further chemical optimization and pharmacological characterization of the M(1) positive allosteric modulator ML169.
AbstractThe M(1) muscarinic acetylcholine receptor is thought to play an important role in memory and cognition, making it a potential target for the treatment of Alzheimer's disease (AD) and schizophrenia. Moreover, M(1) interacts with BACE1 and regulates its proteosomal degradation, suggesting selective M(1) activation could afford both palliative cognitive benefit as well as disease modification in AD. A key challenge in targeting the muscarinic acetylcholine receptors is achieving mAChR subtype selectivity. Our lab has previously reported the M(1) selective positive allosteric modulator ML169. Herein we describe our efforts to further optimize this lead compound by preparing analogue libraries and probing novel scaffolds. We were able to identify several analogues that possessed submicromolar potency, with our best example displaying an EC(50) of 310 nM. The new compounds maintained complete selectivity for the M(1) receptor over the other subtypes (M(2)-M(5)), displayed improved DMPK profiles, and potentiated the carbachol (CCh)-induced excitation in striatal MSNs. Selected analogues were able to potentiate CCh-mediated nonamyloidogenic APPs? release, further strengthening the concept that M(1) PAMs may afford a disease-modifying role in the treatment of AD.
SCZ Keywordsschizophrenia
4J. Med. Chem. 2014 Jul 57: 5620-37
PMID24914612
TitleTetrahydronaphthyridine and dihydronaphthyridinone ethers as positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu?).
AbstractPositive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) represent a promising therapeutic strategy for the treatment of schizophrenia. Starting from an acetylene-based lead from high throughput screening, an evolved bicyclic dihydronaphthyridinone was identified. We describe further refinements leading to both dihydronaphthyridinone and tetrahydronaphthyridine mGlu5 PAMs containing an alkoxy-based linkage as an acetylene replacement. Exploration of several structural features including western pyridine ring isomers, positional amides, linker connectivity/position, and combinations thereof, reveal that these bicyclic modulators generally exhibit steep SAR and within specific subseries display a propensity for pharmacological mode switching at mGlu5 as well as antagonist activity at mGlu3. Structure-activity relationships within a dihydronaphthyridinone subseries uncovered 12c (VU0405372), a selective mGlu5 PAM with good in vitro potency, low glutamate fold-shift, acceptable DMPK properties, and in vivo efficacy in an amphetamine-based model of psychosis.
SCZ Keywordsschizophrenia
5Curr Top Med Chem 2014 -1 14: 304-12
PMID24283972
TitleA unique industrial-academic collaboration towards the next generation of schizophrenia therapeutics.
AbstractThis article describes the unique industrial-academic collaboration that has been running for four years between Janssen Pharmaceutica NV and the Vanderbilt Center for Neuroscience Drug Discovery (VCNDD) towards identifying the next generation of schizophrenia therapeutics. This was a true collaboration, with both entities engaged in chemistry, In vitro pharmacology, DMPK and In vivo behavioral pharmacology, and aligned to deliver a first-in-class clinical candidate (NME) and additional back-up molecules. Notably, a first NME was delivered in a rapid timeframe and targeted the novel mechanism of mGlu5 positive allosteric modulation. As with any true collaboration, both sides brought unique skills to the table--Janssen leveraged deep drug discovery expertise and infrastructure, while Vanderbilt brought deep knowledge of the chemistry and pharmacology of the target in addition to the ability to provide deep scientific insight into the mechanism behind target modulation. In this article, we will discuss the science which drove our collaboration as well as some key lessons learned.
SCZ Keywordsschizophrenia
6ACS Med Chem Lett 2015 Jun 6: 716-20
PMID26157544
TitleDiscovery of VU0409551/JNJ-46778212: An mGlu5 Positive Allosteric Modulator Clinical Candidate Targeting Schizophrenia.
AbstractHerein, we report the structure-activity relationship of a novel series of (2(phenoxymethyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-yl(aryl)methanones as potent, selective, and orally bioavailable metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). On the basis of its robust in vitro potency and in vivo efficacy in multiple preclinical models of multiple domains of schizophrenia, coupled with a good DMPK profile and an acceptable therapeutic window, 17a (VU0409551/JNJ-46778212) was selected as a candidate for further development.
SCZ Keywordsschizophrenia
7Bioorg. Med. Chem. Lett. 2015 Mar 25: 1310-7
PMID25683622
TitleDiscovery and SAR of novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5).
AbstractWe report the discovery and SAR of two novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of several structural features in the western and eastern part of the imidazopyrimidinone core and combinations thereof, revealed compound 4a as a mGlu5 PAM with good in vitro potency and efficacy, acceptable drug metabolism and pharmacokinetic (DMPK) properties and in vivo efficacy in an amphetamine-based model of psychosis. However, the presence of CNS-mediated adverse effects in preclinical species precluded any further in vivo evaluation.
SCZ Keywordsschizophrenia
8Bioorg. Med. Chem. Lett. 2016 May 26: 2289-92
PMID27013388
TitleRe-exploration of the mGlu1 PAM Ro 07-11401 scaffold: Discovery of analogs with improved CNS penetration despite steep SAR.
AbstractThis letter describes the re-exploration of the mGlu1 PAM Ro 07-11401 scaffold through a multi-dimensional, iterative parallel synthesis approach. Unlike recent series of mGlu1 PAMs with robust SAR, the SAR around the Ro 07-11401 structure was incredibly steep (only ?6 of 200 analogs displayed mGlu1 PAM activity), and reminiscent of the CPPHA mGlu5 PAM scaffold. Despite the steep SAR, two new thiazole derivatives were discovered with improved in vitro DMPK profiles and ?3- to 4-fold improvement in CNS exposure (Kps 1.01-1.19); albeit, with a ?3-fold diminution in mGlu1 PAM potency, yet comparable efficacy (?5-fold leftward shift of the glutamate concentration-response curve at 10?M). Thus, this effort has provided additional CNS penetrant mGlu1 PAM tools in a different chemotype than the VU0486321 scaffold. These compounds will permit a better understanding of the pharmacology and therapeutic potential of selective mGlu1 activation, while highlighting the steep SAR challenges that can often be encountered in GPCR allosteric modulator discovery.
SCZ Keywordsschizophrenia
9Bioorg. Med. Chem. Lett. 2016 Apr 26: 1869-72
PMID26988302
TitleLead optimization of the VU0486321 series of mGlu1 PAMs. Part 3. Engineering plasma stability by discovery and optimization of isoindolinone analogs.
AbstractThis Letter describes the further lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs), focused on addressing the recurrent issue of plasma instability of the phthalimide moiety. Here, we evaluated a number of phthalimide bioisosteres, and ultimately identified isoindolinones as the ideal replacement that effectively address plasma instability, while maintaining acceptable mGlu1 PAM potency, DMPK profile, CNS penetration and mGluR selectivity.
SCZ Keywordsschizophrenia
10Bioorg. Med. Chem. Lett. 2016 Feb 26: 751-6
PMID26778256
TitleLead optimization of the VU0486321 series of mGlu(1) PAMs. Part 2: SAR of alternative 3-methyl heterocycles and progress towards an in vivo tool.
AbstractThis Letter describes the further lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs), driven by recent genetic data linking loss of function GRM1 to schizophrenia. Steep and caveat-laden SAR plagues the series, but ultimately potent mGlu1 PAMs (EC50s ?5 nM) have resulted with good DMPK properties (low intrinsic clearance, clean CYP profile, modest Fu) and CNS penetration (Kps 0.25-0.97), along with up to >450-fold selectivity versus mGlu4 and mGlu5.
SCZ Keywordsschizophrenia