Design, Synthesis of Novel, Potent, Selective, Orally Bioavailable Adenosine A2A Receptor Antagonists and Their Biological Evaluation
| Autor: | Azfar Quraishi, Anita Chug, Suraj Menon, Vishal Unadkat, Sujay Basu, Madhav S. Seervi, Vandna Prasad, Sumit Chaudhary, Yogesh D. Shejul, Ganesh Bhat, Sachin Thorat, Ravi K. Bhamidipati, Shariq S. Ansari, Ashwinkumar V. Meru, Rhishikesh Thakare, Kasim A. Mookhtiar, Yogesh Salve, Venkata P. Palle, Minakshi Naykodi, Siddhartha De, Vaibhav Jain, Harish Patil, Indraneel Ghosh, Dinesh A. Barawkar, Meena Patel, Sreekanth R. Rouduri |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Chemistry Antagonist Pharmacology 01 natural sciences Adenosine receptor In vitro 0104 chemical sciences Bioavailability 010404 medicinal & biomolecular chemistry 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology Benzothiazole Pharmacokinetics Drug Discovery Molecular Medicine Solubility ADME |
| Zdroj: | Journal of Medicinal Chemistry. 60:681-694 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.6b01584 |
| Popis: | Our initial structure–activity relationship studies on 7-methoxy-4-morpholino-benzothiazole derivatives featured by aryloxy-2-methylpropanamide moieties at the 2-position led to identification of compound 25 as a potent and selective A2A adenosine receptor (A2AAdoR) antagonist with reasonable ADME and pharmacokinetic properties. However, poor intrinsic solubility and low to moderate oral bioavailability made this series unsuitable for further development. Further optimization using structure-based drug design approach resulted in discovery of potent and selective adenosine A2A receptor antagonists bearing substituted 1-methylcyclohexyl-carboxamide groups at position 2 of the benzothiazole scaffold and endowed with better solubility and oral bioavailability. Compounds 41 and 49 demonstrated a number of positive attributes with respect to in vitro ADME properties. Both compounds displayed good pharmacokinetic properties with 63% and 61% oral bioavailability, respectively, in rat. Further, compound 49 displa... |
| Databáze: | OpenAIRE |
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