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Paramus, NJ, United States

Huang X.,Molecular Pharmacology & Sar Neuroinflammation Disease Biology Unit | Dale E.,15 College Road | Brodbeck R.M.,Molecular Pharmacology & Sar Neuroinflammation Disease Biology Unit | Doller D.,Lundbeck
Current Topics in Medicinal Chemistry | Year: 2014

Drug design necessitates a clear understanding of the phenotypic response to be elicited by a given ligandtarget interaction. This relationship is relatively well understood for classical biological targets of drug action, but for some novel targets, notably those amenable to allosteric modulation, developing such understanding may represent a more challenging task. In order to gain knowledge on the nature of the functional response derived from mGlu4 receptor activation, its molecular and cell biology are reviewed, including signalling pathways involved, receptor localization in central nervous system and beyond, and potential genetic links to disease. Broadly held views for both, orthosteric agonists as well as allosteric modulators, are compared with specific observations for the case of mGlu4 receptor activation via orthosteric and allosteric mechanisms. First, sub-type selectivity and brain penetration of amino acid mGlu4 receptor agonists are discussed, followed by the quantification of functional allosteric effects, the potential role of heterodimers in the functional response, and the observation of supra-physiological efficacy of mGlu4 receptor PAMs. We show that, in our analysis, these attributes differ from those that may be expected by extrapolating from broad knowledge. In addition, recent progress with mGlu4 receptor radioligands and PET ligands is summarized. © 2014 Bentham Science Publishers Source


Wu L.,15 College Road | Lu K.,15 College Road | Packiarajan M.,15 College Road | Jubian V.,15 College Road | And 3 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2012

A novel series of indolyl and dihydroindolyl glycinamides were identified as potent NPY5 antagonists with in vivo activity from screen hit 1. The dihydroindolyl glycinamide 10a significantly inhibits NPY5 agonist induced feeding at a dose of 0.1 mg/kg. The indolyl glycinamide 12c also inhibits NPY5 agonist induced feeding at a dose of 1 mg/kg. Both compounds 10a and 12c represent potential tools for further investigation into the biology of the NPY5 receptor. © 2011 Elsevier Ltd. All rights reserved. Source


Wu L.,15 College Road | Lu K.,15 College Road | Desai M.,15 College Road | Packiarajan M.,15 College Road | And 7 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

Subtype specific ligands are needed to evaluate the therapeutic potential of modulating the brain's neuropeptide Y system. The benzothiazepine glycinamide 1a was identified as an NPY5 antagonist lead. While having acceptable solubility, the compound was found to suffer from high clearance and poor exposure. Optimization efforts are described targeting improvements in potency, microsomal stability, and PK properties. The low microsomal stability and poor PK properties were addressed through the optimization of the sulfonyl urea and replacement of the benzothiazepinone with other N-heteroaryl glycinamides. For example, the analogous benzoxazine glycinamide 2e has improvements in both affinity (human Y5 K i 4 nM vs 1a 27 nM) and microsomal stability (human CL int 2.5 L/min vs 1a 35 L/min). However the brain penetration (B/P 43/430 nM at 10 mg/kg PO) remained an unresolved issue. Further optimization by decreasing the hydrogen bond donating properties and PSA provided potent and brain penetrant NPY5 antagonists such as 5f (human Y5 K i 9 nM, B/P 520/840 nM 10 mg/kg PO). © 2011 Elsevier Ltd. All rights reserved. Source

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