title: Design, Synthesis of Novel, Potent, Selective, Orally Bioavailable Adenosine A2AReceptor Antagonists and Their Biological Evaluation.
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 A2Aadenosine 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 A2Areceptor 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.
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
authors.forename: Sujay
authors.identifier: 0000-0001-7198-325X
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authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
authors.forename: Dinesh A
authors.initials: DA
authors.lastname: Barawkar
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
authors.forename: Sachin
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authors.lastname: Thorat
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
authors.forename: Yogesh D
authors.initials: YD
authors.lastname: Shejul
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
authors.forename: Meena
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authors.lastname: Patel
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
authors.forename: Minakshi
authors.initials: M
authors.lastname: Naykodi
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Jain
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Salve
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
authors.forename: Vandna
authors.initials: V
authors.lastname: Prasad
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
authors.forename: Sumit
authors.initials: S
authors.lastname: Chaudhary
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
authors.forename: Indraneel
authors.initials: I
authors.lastname: Ghosh
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Bhat
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
authors.forename: Azfar
authors.initials: A
authors.lastname: Quraishi
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
authors.forename: Harish
authors.initials: H
authors.lastname: Patil
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
authors.forename: Shariq
authors.initials: S
authors.lastname: Ansari
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
authors.forename: Suraj
authors.initials: S
authors.lastname: Menon
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
authors.forename: Vishal
authors.initials: V
authors.lastname: Unadkat
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
authors.forename: Rhishikesh
authors.initials: R
authors.lastname: Thakare
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
authors.forename: Madhav S
authors.initials: MS
authors.lastname: Seervi
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
authors.forename: Ashwinkumar V
authors.initials: AV
authors.lastname: Meru
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: De
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Bhamidipati
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
authors.forename: Sreekanth R
authors.initials: SR
authors.lastname: Rouduri
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
authors.forename: Venkata P
authors.initials: VP
authors.lastname: Palle
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
authors.forename: Anita
authors.initials: A
authors.lastname: Chug
authors.affiliation: Drug Discovery Facility, Advinus Therapeutics Ltd. , Quantum Towers, Plot-9, Phase-I, Rajiv Gandhi Infotech Park, Hinjawadi, Pune 411 057, India.
authors.forename: Kasim A
authors.initials: KA
authors.lastname: Mookhtiar
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D003511:Cyclohexanols / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D062105:Molecular Docking Simulation; D017208:Rats, Wistar; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C000620973:4-(diethylamino)-N-(4-methoxy-7-morpholino-1,3-benzothiazol-2-yl)-1-methylcyclohexanecarboxamide; D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D052160:Benzothiazoles; D003511:Cyclohexanols; D043705:Receptor, Adenosine A2A; D007980:Levodopa