- Discovery of novel brain permeable and G protein-biased beta-1 adrenergic receptor partial agonists for the treatment of neurocognitive disorders
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The beta-1 adrenergic receptor (ADRB1) is a promising therapeutic target intrinsically involved in the cognitive deficits and pathological features associated with Alzheimer’s disease (AD). Evidence indicates that ADRB1 plays an important role in regulating neuroinflammatory processes, and activation of ADRB1 may produce neuroprotective effects in neuroinflammatory diseases. Novel small molecule modulators of ADRB1, engineered to be highly brain permeable and functionally selective for the G protein with partial agonistic activity, could have tremendous value both as pharmacological tools and potential lead molecules for further preclinical development. The present study describes our ongoing efforts toward the discovery of functionally selective partial agonists of ADRB1 that have potential therapeutic value for AD and neuroinflammatory disorders, which has led to the identification of the molecule STD-101-D1. As a functionally selective agonist of ADRB1, STD-101-D1 produces partial agonistic activity on G protein signaling with an EC50 value in the low nanomolar range, but engages very little beta-arrestin recruitment compared to the unbiased agonist isoproterenol. STD-101-D1 also inhibits the tumor necrosis factor α (TNFα) response induced by lipopolysaccharide (LPS) both in vitro and in vivo, and shows high brain penetration. Other than the therapeutic role, this newly identified, functionally selective, partial agonist of ADRB1 is an invaluable research tool to study mechanisms of G protein-coupled receptor signal transduction.
- Yi, Bitna,Jahangir, Alam,Evans, Andrew K.,Briggs, Denise,Ravina, Kristine,Ernest, Jacqueline,Farimani, Amir B.,Sun, Wenchao,Rajadas, Jayakumar,Green, Michael,Feinberg, Evan N.,Pande, Vijay S.,Shamloo, Mehrdad
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- METHOD OF IMPROVING COGNITION AND SOCIAL BEHAVIOR IN HUMANS HAVING DEFICITS THEREIN DUE TO NEURODEGENERATIVE DISORDERS AND COMPOUNDS AND COMPOSITIONS THEREFOR
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A β1-ADR agonist prodrug compound, which is hydrolysable in vivo to release a β1-ADR agonist compound, and which prodrug compound contains a group which imparts greater lipophilicity and CNS bioavailability to the prodrug compound relative to the β1-ADR agonist compound.
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Paragraph 0133; 0136
(2016/08/03)
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- BETA-3 RECEPTOR LIGANDS AND THEIR USE IN THERAPY
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The present invention relates to new compounds, ligands of the beta-3 adrenergic receptor, their preparation and their use in therapy or as research tools for said receptor; the invention also relates to a process for the preparation of the compounds of the invention and the use of inverse agonists of the beta-3 adrenergic receptor as medicaments.
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Page/Page column 12
(2010/04/23)
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- Azolidines as beta-3 adrenergic receptor agonists
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This invention provides compounds of Formula I having the structure wherein, A, X, Y, Z, W, R1, R2, R3, R4, R5, and R6 are as defined hereinbefore or a pharmaceutically acceptable salt thereof, which are useful in treating or inhibiting metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, glaucoma, ocular hypertension and frequent urination; and are particularly useful in the treatment or inhibition of type II diabetes.
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- HETEROCYCLIC BETA-3 ADRENERGIC RECEPTOR AGONISTS
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This invention provides compounds of Formula I having the structure U, V, W, X, and Y are as defined hereinbefore, or a pharmaceutically acceptable salt thereof, which are useful in treating or inhibiting metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, glaucoma, ocular hypertension and frequent urination; and are particularly useful in the treatment or inhibition of type II diabetes.
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- Initial structure-activity relationship of a novel class of nonpeptidyl GnRH receptor antagonists: 2-arylindoles
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A nonpeptidyl GnRH receptor antagonist (1), with a unique 2-arylindole core, was identified through the Merck in-house screening for binding affinity on the rat GnRH receptor. SAR studies directed toward the alkoxy-ethanolamine and 2-aryl groups resulted in a simpler lead structure with improved activity. This compound 50 exhibits a 60-fold improvement in binding activity over our initial lead 1.
- Chu, Lin,Hutchins, Jennifer E.,Weber, Ann E.,Lo, Jane-Ling,Yang, Yi-Tien,Cheng, Kang,Smith, Roy G.,Fisher, Michael H.,Wyvratt, Matthew J.,Goulet, Mark T.
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p. 509 - 513
(2007/10/03)
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- Potent, selective aminothiazolidinediones agonists of the human β3 Adrenergic receptor
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A cloned human β3 adrenergic receptor assay was used to identify potent and selective β3 agonists. The thiazolidinedione moiety has been identified as a new pharmacophore for the human β3 adrenergic receptor. The versatility of the thiazolidinedione pharmacophore was demonstrated in both the arylethanolamine and phenylpropanolamine families of β3 agonists, where potent and selective compounds have been synthesized. Thiazolidinedione 20, a potent and selective human β3 agonist, increased thermogenesis and lowered plasma glucose levels in the db/db mice.
- Malamas,Largis,Gunawan,Li,Tillett,Han,Mulvey
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p. 164 - 177
(2007/10/03)
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- Potent, selective benzenesulfonamide agonists of the human β3 adrenergic receptor
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A cloned human β3 adrenergic receptor assay was used to identify phenoxypropanolamine agonist 1. SAR, studies led to the identification of benzenesulfonamide derivative 20, a 6.3 nM β3 agonist which shows 30-fold selectivity for β3 agonist activity over β1 and β2 receptor binding. Further refinement of this lead provided 4-bromo derivative 39, a subnanomolar agonist with 660-fold and 230-fold selectivity over β1 and β2, respectively.
- Weber, Ann E.,Mathvink, Robert J.,Perkins, Leroy,Hutchins, Jennifer E.,Candelore, Mari R.,Tota, Laurie,Strader, Catherine D.,Wyvratt, Matthew J.,Fisher, Michael H.
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p. 1101 - 1106
(2007/10/03)
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- Synthesis and Properties of Optically Active α-Alkyl-γ-aryloxymethyl-γ-lactones as Chiral Dopants for Ferroelectric Liquid Crystals
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Optically active α-alkyl-γ-aryloxymethyl-γ-lactones were synthesized from chiral epichlorohydrin in short steps and found to be superior chiral dopants for ferroelectric liquid crystals (FLCs).
- Sakaguchi, Kazuhiko,Shiomi, Yutaka,Kitamura, Tohru,Takehira, Yoshikazu,Koden, Mitsuhiro,et al.
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p. 1109 - 1112
(2007/10/02)
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- Phenol esters.
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A phenol ester of xamoterol of the formula: wherein X is a methylene radical or a direct bond, R1 is a hydrogen atom or an alkyl or alkenyl radical of 3 to 8 carbon atoms, and R2 and R3, which may be the same or different, are each a 1--4C alkyl radical;
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