- A synthetic bone morphogenetic protein receptor inhibitors
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The invention discloses a method for synthesizing a bone morphogenetic protein receptor inhibitor, and solves the problem of long inhibitor synthesis route in the prior art. The method comprises the following steps: 1, obtaining an intermediate represented by formula (III) shown in the specification, wherein R1 in the formula (III) can be a first formula or a second formula also shown in the specification; 2, adding 5-bromoquinoline to the intermediate represented by formula (III), adding potassium acetate and palladium acetate, adding N,N-dimethyl acetamide, reacting, and cooling to room temperature; and 3, adding water to precipitate a solid when the R1 is the first formula, drying, and separating to obtain a product 1; and extracting the above obtained reaction solution by ethyl acetate when the R1 is the second formula, drying the obtained organic phase to remove a solvent, separating to obtain the product 1, dissolving the product 1 in methanol, adding concentrated hydrochloric acid, reacting to precipitate a solid, carrying out pumping filtration, washing, and drying to obtain a product 2. The method has the advantages of short preparation steps, low price of adopted raw materials, and high yield of target products.
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Paragraph 0037; 0041; 0044
(2017/10/06)
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- Synthesis and structure-activity relationships of a novel and selective bone morphogenetic protein receptor (BMP) inhibitor derived from the pyrazolo[1.5-a]pyrimidine scaffold of Dorsomorphin: The discovery of ML347 as an ALK2 versus ALK3 selective MLPCN probe
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A structure-activity relationship of the 3- and 6-positions of the pyrazolo[1,5-a]pyrimidine scaffold of the known BMP inhibitors dorsomorphin, 1, LDN-193189, 2, and DMH1, 3, led to the identification of a potent and selective compound for ALK2 versus ALK3. The potency contributions of several 3-position substituents were evaluated with subtle structural changes leading to significant changes in potency. From these studies, a novel 5-quinoline molecule was identified and designated an MLPCN probe molecule, ML347, which shows >300-fold selectivity for ALK2 and presents the community with a selective molecular probe for further biological evaluation.
- Engers, Darren W.,Frist, Audrey Y.,Lindsley, Craig W.,Hong, Charles C.,Hopkins, Corey R.
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supporting information
p. 3248 - 3252
(2013/06/27)
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- Structure-activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors
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A structure-activity relationship study of dorsomorphin, a previously identified inhibitor of SMAD 1/5/8 phosphorylation by bone morphogenetic protein (BMP) type 1 receptors ALK2, 3, and 6, revealed that increased inhibitory activity could be accomplished by replacing the pendent 4-pyridine ring with 4-quinoline. The activity contributions of various nitrogen atoms in the core pyrazolo[1,5-a]pyrimidine ring were also examined by preparing and evaluating pyrrolo[1,2-a]pyrimidine and pyrazolo[1,5-a]pyridine derivatives. In addition, increased mouse liver microsome stability was achieved by replacing the ether substituent on the pendent phenyl ring with piperazine. Finally, an optimized compound 13 (LDN-193189 or DM-3189) demonstrated moderate pharmacokinetic characteristics (e.g., plasma t1/2 = 1.6 h) following intraperitoneal administration in mice. These studies provide useful molecular probes for examining the in vivo pharmacology of BMP signaling inhibition.
- Cuny, Gregory D.,Yu, Paul B.,Laha, Joydev K.,Xing, Xuechao,Liu, Ji-Feng,Lai, Carol S.,Deng, Donna Y.,Sachidanandan, Chetana,Bloch, Kenneth D.,Peterson, Randall T.
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supporting information; scheme or table
p. 4388 - 4392
(2009/04/06)
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