- Pharmacophore Mapping of Thienopyrimidine-Based Monophosphonate (ThP-MP) Inhibitors of the Human Farnesyl Pyrophosphate Synthase
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The human farnesyl pyrophosphate synthase (hFPPS), a key regulatory enzyme in the mevalonate pathway, catalyzes the biosynthesis of the C-15 isoprenoid farnesyl pyrophosphate (FPP). FPP plays a crucial role in the post-translational prenylation of small GTPases that perform a plethora of cellular functions. Although hFPPS is a well-established therapeutic target for lytic bone diseases, the currently available bisphosphonate drugs exhibit poor cellular uptake and distribution into nonskeletal tissues. Recent drug discovery efforts have focused primarily on allosteric inhibition of hFPPS and the discovery of non-bisphosphonate drugs for potentially treating nonskeletal diseases. Hit-to-lead optimization of a new series of thienopyrimidine-based monosphosphonates (ThP-MPs) led to the identification of analogs with nanomolar potency in inhibiting hFPPS. Their interactions with the allosteric pocket of the enzyme were characterized by crystallography, and the results provide further insight into the pharmacophore requirements for allosteric inhibition.
- Park, Jaeok,Leung, Chun Yuen,Matralis, Alexios N.,Lacbay, Cyrus M.,Tsakos, Michail,Fernandez De Troconiz, Guillermo,Berghuis, Albert M.,Tsantrizos, Youla S.
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p. 2119 - 2134
(2017/03/17)
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- Thieno[2,3-d]pyrimidines and -[1,3]oxazines as glutamate antagonists and investigations on the inhibitory potency toward human leukocyte elastase
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(Chemical Equation Presented) A series of fused thiophene derivatives, that is, representatives of thieno[2,3-d]pyrimidines, thieno[2,3-d][1,3]oxazines and thieno[2,3-d][1,3]thiazines, with the common 5-methyl-6-phenyl substitution pattern was synthesized. The target compounds, e.g., 7 or 8, were designed as cyclic analogs of ethyl 2-amino-4-methyl-5-phenylthiophene-3-carboxylate, an antagonist at the GluR6 kainate receptor. Thieno[2,3-d][1,3]oxazin-4-one 2 (R = C2H5) was identified as new a potent inhibitor (IC50 = 17 lM) of this receptor subtype. The inhibitory potency of 2 (R = C2H5) against human leukocyte elastase was also examined. The compound was characterized as a noncovalent inhibitor with an IC50 value of 8.8 μM.
- Briel, Detlef,Rybak, Anastasiya,Kronbach, Christiane,Unverferth, Klaus,Gonzalez Tanarro, Camino M.,Guetschow, Michael
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scheme or table
p. 634 - 639
(2010/08/20)
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- Thieno[2,3-d]pyrimidines as antagonists of the glutamate receptors
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Although the function of the kainate receptors in the brain is still not clear, they are increasingly defined as targets in the development of new classes of anti-epileptics. The thienopyrimidines described in this report were tested for their antagonisti
- Briel,Rybak,Kronbach,Unverferth
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experimental part
p. 823 - 826
(2009/04/10)
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