Design, Synthesis of Novel, Potent, Selective, Orally Bioavailable Adenosine A(2A) Receptor Antagonists and Their Biological Evaluation

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(2A)AdoR) antagonist with reasonable AD...

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Published inJournal of medicinal chemistry Vol. 60; no. 2; pp. 681 - 694
Main Authors Basu, Sujay, Barawkar, Dinesh A., Thorat, Sachin, Shejul, Yogesh D., Patel, Meena, Naykodi, Minakshi, Jain, Vaibhav, Salve, Yogesh, Prasad, Vandna, Chaudhary, Sumit, Ghosh, Indraneel, Bhat, Ganesh, Quraishi, Azfar, Patil, Harish, Ansari, Shariq, Menon, Suraj, Unadkat, Vishal, Thakare, Rhishikesh, Seervi, Madhav S., Meru, Ashwinkumar V., De, Siddhartha, Bhamidipati, Ravi K., Rouduri, Sreekanth R., Palle, Venkata P., Chug, Anita, Mookhtiar, Kasim A.
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 26.01.2017
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
INHIBITION
ACCURATE DOCKING
DRUGS
PROGRESS
GLIDE
DERIVATIVES
DISCOVERY
AGONIST
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Summary: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(2A)AdoR) 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-methylcydohexyl-carboxamide groups at position 2 of the benzotbiazole 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.6b01584