28560-51-2Relevant academic research and scientific papers
Identification of Novel Fragments Binding to the PDZ1-2 Domain of PSD-95
Zang, Jie,Ye, Fei,Solbak, Sara M. ?.,H?j, Lars J.,Zhang, Mingjie,Bach, Anders
supporting information, p. 949 - 954 (2020/12/31)
Inhibition of PSD-95 has emerged as a promising strategy for the treatment of ischemic stroke, as shown with peptide-based compounds that target the PDZ domains of PSD-95. In contrast, developing potent and drug-like small molecules against the PSD-95 PDZ domains has so far been unsuccessful. Here, we explore the druggability of the PSD-95 PDZ1-2 domain and use fragment screening to investigate if this protein is prone to binding small molecules. We screened 2500 fragments by fluorescence polarization (FP) and validated the hits by surface plasmon resonance (SPR), including an inhibition counter-test, and found four promising fragments. Three ligand efficient fragments were shown by 1H,15N HSQC NMR to bind in the small hydrophobic P0 pockets of PDZ1-2, and one of them underwent structure-activity relationship (SAR) studies. Overall, we demonstrate that fragment screening can successfully be applied to PDZ1-2 of PSD-95 and disclose novel fragments that can serve as starting points for optimization towards small-molecule PDZ domain inhibitors.
Quinuclidine derivatives and their use as muscarinic M3 receptor ligands
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, (2008/06/13)
A compound according to formula (I) wherein: is a phenyl ring, a C4 to C9 heteroaromatic compound containing one or more heteroatoms, or a naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or biphenyl group; R1, R2 and R3 each independently represent a hydrogen or halogen atom, or a hydroxy group, or a phenyl, —OR4, —SR4, —NR4R5, —NHCOR4, —CONR4R5, —CN, —NO2, —COOR4 or —CF3 group, or a straight or branched lower alkyl group which may optionally be substituted, for example, with a hydroxy or alcoxy group, wherein R4 and R5 each independently represent a hydrogen atom, straight or branched lower alkyl group, or together form an alicyclic ring; or R1 and R2 together form an aromatic, alicyclic or heterocyclic ring; n is an integer from 0 to 4; A represents a —CH2—, —CH═CR6, —CR6=CH—, —CR6R7—, —CO—, —O—, —S—, —S(O)—, SO2 or —NR6— group, wherein R6 and R7 each independently represent a hydrogen atom, straight or branched lower alkyl group, or R6 and R7 together form an alicyclic ring; m is an integer from 0 to 8; provided that when m=0, A is not —CH2—; p is an integer from 1 to 2 and the substitution in the azoniabicyclic ring may be in the 2, 3 or 4 position including all possible configurations of the asymmetric carbons; B represents a group of formula i) or ii): wherein R10 represents a hydrogen atom, a hydroxy or methyl group; and R8 and R9 each independently represents wherein R11 represents a hydrogen or halogen atom, or a straight or branched lower alkyl group and Q represents a single bond, —CH2—, —CH2—CH2—, —O—, —O—CH2—, —S—, —S—CH2— or —CH═CH—, and when i) or ii) contain a chiral centre they may represent either configuration; X represents a pharmaceutically acceptable anion of a mono or polyvalent acid, which shows high affinity for muscarinic M3 receptors (Hm3).
A Study of Some Thiophene Analogues of Glycolic Acid
Jeffries, Alfred T.,Moore, Kenneth C.,Ondeyka, Debra M.,Springsteen, Arthur W.,MacDowell, Denis W.H.
, p. 2885 - 2889 (2007/10/02)
Reaction of phenyl(3-thienyl)glycolic acid (1) with AlCl3 in benzene solution leads to the formation of 4H-indenothiophene-4-carboxylic acid (2) whereas analogous reaction of phenyl(2-thienyl)glycolic acid (4) produces no indenothiophene but only a mixture of 5 and 6.In the case of di-(2-thienyl)glycolic acid (14b) and di-(3-thienyl)glycolic acid (16b) analogous results are obtained, with the former leading to the formation of 15 and the latter producing 17.In the case of the (benzothienyl)phenylglycolic analogues of 1 and 4 the acids were unstable to heat so that the esters, ethyl (2-benzothienyl)phenylglycolate (21) and ethyl (3-benzothienyl)phenylglycolate (20), upon treatment with AlCl3 in benzene led to cyclized products only.The former gave 23 which was saponified and decarboxylated to yield 25 and compared with an authentic sample obtained by synthesis.Ester 20 similarly gave 22 which was similarly converted to the known 24.A mechanistic explanation of these findings is proposed.
