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J Med Chem. 2017 Jan 26;60(2):681-694. doi: 10.1021/acs.jmedchem.6b01584. Epub 2017 Jan 17.

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

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1
Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.

Abstract

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 displayed oral efficacy in 6-OHDA lesioned rat model of Parkinson diseases.

PMID:
28055204
DOI:
10.1021/acs.jmedchem.6b01584
[Indexed for MEDLINE]

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