76263-24-6Relevant articles and documents
BISPECIFIC ANTAGONISTS OF RETINOL-BINDING PROTEIN 4 THAT STABILIZE TRANSTHYRETIN TETRAMERS, THEIR PREPARATION, AND USE IN THE TREATMENT OF COMMON AGE-RELATED COMORBIDITIES
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, (2022/02/05)
The present invention provides a compound having the structure: Formula (I) wherein X is CR6 or N; R1, R2, R3, R4, and R6 are each independently -H, -F, -Cl, -Br, -I, -NO2, -CN, -CF3, -CF2H, -OCF3, -(alkyl), -(haloalkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -(cycloalkyl), -(cycloalkylalkyl), -(heteroalkyl), heterocycle, heterocycloalkyl, -(alkylheteroalkyl), -(alkylaryl), -OH, -OAc, -0-(alkyl), -0-(alkenyl), -0-(alkynyl), -0-(aryl), -O- (heteroaryl), -SH, -S-(alkyl), -S-(alkenyl), -S-(alkynyl), -S- (aryl), -S-(heteroaryl), -NH2, -NH-(alkyl), -NH-(alkenyl), -NH- (alkynyl), -NH-(aryl), -NH-(heteroaryl), -C(O)R7, -S(O)R7, SO2R7, -NHSO2R7, -OC(O)R7, -SC(O)R7, -NHC(O)R8 or -NHC(S)R8, wherein R7 is, H, -(alkyl), -OH, -O(alkyl), -NH2, -NH(alkyl) or -N(alkyl)2, and wherein R6 is, -(alkyl), -O-(alkyl), -NH2, -NH(alkyl) or N(alkyl)2; Y is O, S, Ν, ΝΗ, or a bond; Z is O, S, N, NH, (CH2)O, or a bond; R5 is H, OH, halogen, alkyl, or R5 is (CH2)P and is bound to Y when Y is N to form a ring together with Z; o and p are independently 0, 1, 2, or 3; m and n are independently 0, 1, 2, 3, or 4; A, C, and D are each independently N or CR9; R9 is H, halogen, -OH, alkyl, cycloalkyl, cycloalkylalkyl, -O-(alkyl), -S-(alkyl), -NH2, -NH(alkyl), NH(alkyl)2, -CO2H, -CO(O-alkyl); B and E are N, CR9, or CFG wherein at least one of B or E is CFG; F is absent or present, and when present is Formula (II), Formula (III) G is H, substituted or unsubstituted monocycle, bicycle, heteromonocycle, heterobicycle, aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, CO2H, COOR10, OH, OR10, NH2, NHR10, NR10R11, SO2 (alkyl), SO2 (cycloalkyl), SO2(cycloalkylalkyl), CH2NHR10, CH2NR10R11, or CH2COOR10, wherein each R10 R11 are each independently H, alkyl, cycloalkyl, -C(O)-alkyl, -C(O)-cycloalkyl,-C(O)OH, -C(O)-O- alkyl, -C(O)-O-cycloalkyl, -C(O)NH2, -C(O)NH(alkyl), - C(O)NH(cycloalkyl), -C(O)N(alkyl)2, -CH2NH(alkyl), -CH2COOH, - SO2CH3, -OH, -O(alkyl), -NH2, -NH(alkyl), -N(alkyl)2, or a pharmaceutically acceptable salt thereof.
Design, synthesis, and evaluation of nonretinoid retinol binding protein 4 antagonists for the potential treatment of atrophic age-related macular degeneration and stargardt disease
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
, p. 7731 - 7757 (2015/01/09)
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%.
Process for preparing 3-phenoxy-1-azetidines and carboxamide derivatives
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, (2008/06/13)
An improved process is disclosed for preparing 3-phenoxyazetidines which utilizes a phase transfer catalyst to add the phenoxy group to azetidine blocked in the 1-position by a diphenylmethane group and utilizes a stabilizing tertiary amine base to prevent dimerization during hydrogenolysis to remove the blocking group. The crude product containing diphenylmethane may be used without purification to prepare 3-phenoxy-1-azetidinecarboxamides.