- Design, Synthesis, and Preclinical Efficacy of Novel Nonretinoid Antagonists of Retinol-Binding Protein 4 in the Mouse Model of Hepatic Steatosis
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Retinol-binding protein 4 (RBP4) serves as a transporter for all-trans-retinol (1) in the blood, and it has been proposed to act as an adipokine. Elevated plasma levels of the protein have been linked to diabetes, obesity, cardiovascular diseases, and nonalcoholic fatty liver disease (NAFLD). Recently, adipocyte-specific overexpression of RBP4 was reported to cause hepatic steatosis in mice. We previously identified an orally bioavailable RBP4 antagonist that significantly lowered RBP4 serum levels in Abca4-/- knockout mice with concomitant normalization of complement system protein expression and reduction of bisretinoid formation within the retinal pigment epithelium. We describe herein the discovery of novel RBP4 antagonists 48 and 59, which reduce serum RBP4 levels by >80% in mice upon acute oral dosing. Furthermore, 59 demonstrated efficacy in the transgenic adi-hRBP4 murine model of hepatic steatosis, suggesting that RBP4 antagonists may also have therapeutic utility for the treatment of NAFLD.
- Cioffi, Christopher L.,Racz, Boglarka,Varadi, Andras,Freeman, Emily E.,Conlon, Michael P.,Chen, Ping,Zhu, Lei,Kitchen, Douglas B.,Barnes, Keith D.,Martin, William H.,Pearson, Paul G.,Johnson, Graham,Blaner, William S.,Petrukhin, Konstantin
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p. 5470 - 5500
(2019/06/07)
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- Bicyclic [3.3.0]-Octahydrocyclopenta[c]pyrrolo Antagonists of Retinol Binding Protein 4: Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt Disease
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Antagonists of retinol-binding protein 4 (RBP4) impede ocular uptake of serum all-trans retinol (1) and have been shown to reduce cytotoxic bisretinoid formation in the retinal pigment epithelium (RPE), which is associated with the pathogenesis of both dry age-related macular degeneration (AMD) and Stargardt disease. Thus, these agents show promise as a potential pharmacotherapy by which to stem further neurodegeneration and concomitant vision loss associated with geographic atrophy of the macula. We previously disclosed the discovery of a novel series of nonretinoid RBP4 antagonists, represented by bicyclic [3.3.0]-octahydrocyclopenta[c]pyrrolo analogue 4. We describe herein the utilization of a pyrimidine-4-carboxylic acid fragment as a suitable isostere for the anthranilic acid appendage of 4, which led to the discovery of standout antagonist 33. Analogue 33 possesses exquisite in vitro RBP4 binding affinity and favorable drug-like characteristics and was found to reduce circulating plasma RBP4 levels in vivo in a robust manner (>90%).
- Cioffi, Christopher L.,Racz, Boglarka,Freeman, Emily E.,Conlon, Michael P.,Chen, Ping,Stafford, Douglas G.,Schwarz, Daniel M.C.,Zhu, Lei,Kitchen, Douglas B.,Barnes, Keith D.,Dobri, Nicoleta,Michelotti, Enrique,Cywin, Charles L.,Martin, William H.,Pearson, Paul G.,Johnson, Graham,Petrukhin, Konstantin
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p. 5863 - 5888
(2015/08/24)
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- 4-PHENYLPIPERIDINES, THEIR PREPARATION AND USE
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The present invention provides a compound having the structure: (structurally represented) wherein R1, R2, R3, R4, and R5 are each independently H, halogen, CF3 or C1-C4 alkyl; R6 is H, OH, or halogen; B is a substituted or unsubstituted heterobicycle, pyridazine, pyrazole, pyrazine, thiadiazole, or triazole, wherein the heterobicycle is other than chloro substituted indole; and the pyrazole, when substituted, is substituted with other than trifluoromethyl, or a pharmaceutically acceptable salt theref.
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Page/Page column 102; 103
(2014/10/04)
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- Design, synthesis, and evaluation of nonretinoid retinol binding protein 4 antagonists for the potential treatment of atrophic age-related macular degeneration and stargardt disease
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Accumulation of lipofuscin in the retina is associated with pathogenesis of atrophic age-related macular degeneration and Stargardt disease. Lipofuscin bisretinoids (exemplified by N-retinylidene-N-retinylethanolamine) seem to mediate lipofuscin toxicity. Synthesis of lipofuscin bisretinoids depends on the influx of retinol from serum to the retina. Compounds antagonizing the retinol-dependent interaction of retinol-binding protein 4 (RBP4) with transthyretin in the serum would reduce serum RBP4 and retinol and inhibit bisretinoid formation. We recently showed that A1120 (3), a potent carboxylic acid based RBP4 antagonist, can significantly reduce lipofuscin bisretinoid formation in the retinas of Abca4-/-mice. As part of the NIH Blueprint Neurotherapeutics Network project we undertook the in vitro exploration to identify novel conformationally flexible and constrained RBP4 antagonists with improved potency and metabolic stability. We also demonstrate that upon acute and chronic dosing in rats, 43, a potent cyclopentyl fused pyrrolidine antagonist, reduced circulating plasma RBP4 protein levels by approximately 60%.
- Cioffi, Christopher L.,Dobri, Nicoleta,Freeman, Emily E.,Conlon, Michael P.,Chen, Ping,Stafford, Douglas G.,Schwarz, Daniel M. C.,Golden, Kathy C.,Zhu, Lei,Kitchen, Douglas B.,Barnes, Keith D.,Racz, Boglarka,Qin, Qiong,Michelotti, Enrique,Cywin, Charles L.,Martin, William H.,Pearson, Paul G.,Johnson, Graham,Petrukhin, Konstantin
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p. 7731 - 7757
(2015/01/09)
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- Synthesis and SAR study of 4-arylpiperidines and 4-aryl-1,2,3,6- tetrahydropyridines as 5-HT2C agonists
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A series of substituted 4-arylpiperidines and a smaller family of 4-aryl-1,2,3,6-tetrahydropyridines were synthesized and their biological activity at the 5-HT2C receptor studied to determine whether either series showed noteworthy agonist activity. Structure-activity relationships were developed from the performed receptor binding assays and functional studies, and the results of the analysis are presented herein.
- Conway, Richard J.,Valant, Celine,Christopoulos, Arthur,Robertson, Alan D.,Capuano, Ben,Crosby, Ian T.
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supporting information; experimental part
p. 2560 - 2564
(2012/05/05)
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- 11-BETA HSD1 INHIBITORS
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This invention relates to inhibiting 11βHSD1.
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Page/Page column 147-148
(2008/06/13)
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- Piperazinylacylpiperidine derivatives, their preparation and therapeutic use thereof
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The invention relates to substituted 1-piperazinylacylpiperidine derivatives of general formula (I) in which: n is 1 or 2; p is 1 or 2; R1 represents a halogen atom; a trifluoromethyl radical; a (C1-C4)alkyl; a (C1-C4)alkoxy; a trifluoromethoxy radical; R2 represents a hydrogen atom or a halogen atom; R3 represents a hydrogen atom; a group —OR5; a group —CH2OR5; a group —NR6R7; a group —NR8COR9; a group —NR8CONR10R11; a group —CH2NR12R13; a group —CH2NR8CONR14R15; a (C1-C4)alkoxycarbonyl; a group —CONR16R17; or else R3 constitutes a double bond between the carbon atom to which it is attached and the adjacent carbon atom of the piperidine ring; R4 represents an aromatic group selected from: the said aromatic groups being unsubstituted or being mono- or disubstituted by a substituent selected independently from a halogen atom; a (C1-C4)alkyl; a (C1-C4)alkoxy; a trifluoromethyl radical; Preparation process and therapeutic application.
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Page/Page column 12
(2008/06/13)
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- Diphenylalkyl-tetrahydropyridines, process for their preparation, and pharmaceutical compositions containing them
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PCT No. PCT/FR97/02289 Sec. 371 Date Jul. 27, 1999 Sec. 102(e) Date Jul. 27, 1999 PCT Filed Dec. 11, 1997 PCT Pub. No. WO98/25904 PCT Pub. Date Jun. 18, 1998The invention relates to compounds of the formula in which: Y is -CH- or -N-; R1 is a halogen or a
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- 1-Phenylalkyl-1,2,3,6-tetrahydropyridines for treating Alzheimer's disease
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PCT No. PCT/FR97/02286 Sec. 371 Date Jul. 27, 1999 Sec. 102(e) Date Jul. 27, 1999 PCT Filed Dec. 12, 1997 PCT Pub. No. WO98/25903 PCT Pub. Date Jun. 18, 1998The invention relates to compounds of the formula in which: Y is -CH- or -N-; R1 is hydrogen, a ha
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