- A Thieno[2,3- d]pyrimidine Scaffold Is a Novel Negative Allosteric Modulator of the Dopamine D2 Receptor
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Recently, a novel negative allosteric modulator (NAM) of the D2-like dopamine receptors 1 was identified through virtual ligand screening. This ligand comprises a thieno[2,3-d]pyrimidine scaffold that does not feature in known dopaminergic ligands. Herein, we provide pharmacological validation of an allosteric mode of action for 1, revealing that it is a NAM of dopamine efficacy and identify the structural determinants of this allostery. We find that key structural moieties are important for functional affinity and negative cooperativity, while functionalization of the thienopyrimidine at the 5- and 6-positions results in analogues with divergent cooperativity profiles. Successive compound iterations have yielded analogues exhibiting a 10-fold improvement in functional affinity, as well as enhanced negative cooperativity with dopamine affinity and efficacy. Furthermore, our study reveals a fragment-like core that maintains low μM affinity and robust negative cooperativity with markedly improved ligand efficiency.
- Fyfe, Tim J.,Zarzycka, Barbara,Lim, Herman D.,Kellam, Barrie,Mistry, Shailesh N.,Katrich, Vsevolod,Scammells, Peter J.,Lane, J. Robert,Capuano, Ben
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p. 174 - 206
(2018/05/14)
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- Synthesis and biological evaluation of novel condensed pyrimidinylmethylsulfinylbenzimidazoles as antiulcer agent
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Current therapies to treat gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), and other acid-related diseases either prevent stimulation of the parietal cell (H2-receptor antagonists) or inhibit gastric H+/K+/s
- Dudhe, Prashik B.,Jain, Kishor S.,Raskar, Vikas K.,Deodhe, Atul S.,Patel, Jasminkumar G.,Phoujdar, Manisha S.,Kathiravan, Muthu K.
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p. 3719 - 3727
(2013/07/26)
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- A novel microwave-assisted green synthesis of condensed 2-substituted-pyrimidin-4(3H)-ones under solvent-free conditions
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A rapid microwave-assisted green chemical synthesis of condensed 2-substituted-pyrimidin-4(3H)-ones 3, 4, and 5 involving the condensation of a variety of nitriles with o-aminoesters of thiophene 2a-e, benzene 2f, dimethoxybenzene 2g and quinazolinone 2h in the presence of catalytic amount of HCl alone or with the Lewis acid AlCl3 under solvent-free conditions, is described for the first time. This novel and clean one-pot methodology, which is characterized by very short reaction times and easy workup procedures, can be exploited to generate a diverse library of condensed pyrimidine heterocycles.
- Jain, Kishor S.,Bariwal, Jitender B.,Phoujdar, Manisha S.,Nagras, Madhuri A.,Amrutkar, Rakesh D.,Munde, Manoj K.,Tamboli, Riyaj S.,Khedkar, Samrat A.,Khiste, Rahul H.,Vidyasagar, Nikhil C.,Dabholkar, Vinit V.,Kathiravan
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p. 178 - 185
(2009/07/19)
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- Synthesis and antihyperlipidemic activity of some novel condensed 2-chloroalkyl-4-chloro/hydroxy-5,6-disubstituted pyrimidines
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Synthesis and antihyperlipidemic activity of a series of novel condensed 2-chloroalkyl-4-chloro/hydroxy-5,6-di-substituted pyrimidines are described. The design of these compounds is based on the earlier QSAR study on the antihyperlipidemic 2-substituted
- Kathiravan, Matthu K.,Shishoo, Chamanlal J.,Kumar, Krishnan Girish,Roy, Saroj Kumar,Mahadik, Kakasheb R.,Kadam, Shivajirao S.,Jain, Kishor S.
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p. 599 - 606
(2008/03/13)
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- THIENOPYRIMIDINE DERIVATIVES AS POTASSIUM CHANNEL INHIBITORS
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The present invention provides thienopyrimidine compounds which are potasium channels inhibitors. Pharmaceutical compositions comprising the compounds and their use in the treatment of arrhythmia are also provided.
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- Synthesis and pharmacological study of antihyperlipaemic activity of 2-substituted thieno(2,3-d)pyrimidin-4(3H)-ones
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A series of 2-substituted thieno(2,3-d)pyrimidin-4-(3H)-ones (1-15) was prepared by the reaction of thiophene ortho-aminoester (IV) with a variety of nitriles (V) under acidic conditions, and screened for antihyperlipaemic activity in various and animals
- Shishoo,Devani,Bhadti,Jain,Rathod,Goyal,Gandhi,Patel,Naik
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p. 567 - 572
(2007/10/02)
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