Design, Synthesis of Novel, Potent, Selective, Orally Bioavailable Adenosine A2A Receptor Antagonists and Their Biological Evaluation

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• 作者：Sujay BasuDinesh A. Barawkar ; Sachin Thorat ; Yogesh D. Shejul ; Meena Patel ; Minakshi Naykodi ; Vaibhav Jain ; Yogesh Salve ; Vandna Prasad ; Sumit Chaudhary ; Indraneel Ghosh ; Ganesh Bhat ; Azfar Quraishi ; Harish Patil ; Shariq Ansari ; Suraj Menon ; Vishal Unadkat ; Rhishikesh Thakare ; Madhav S. Seervi ; Ashwinkumar V. Meru ; Siddhartha De ; Ravi K. Bhamidipati ; Sreekanth R. Rouduri ; Venkata P. Palle ; Anita Chug ; Kasim A. Mookhtiar
• 刊名：Journal of Medicinal Chemistry
• 出版年：2017
• 出版时间：January 26, 2017
• 年：2017
• 卷：60
• 期：2
• 页码：681-694
• 全文大小：655K
• ISSN：1520-4804

文摘

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 A_2A adenosine receptor (A_2AAdoR) 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 A_2A 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 displayed oral efficacy in 6-OHDA lesioned rat model of Parkinson diseases.