title: Design, synthesis and pharmacological evaluation of novel polycyclic heteroarene ethers as PDE10A inhibitors: Part I.
abstract: We report analogue-based rational design and synthesis of two novel series of polycyclic heteroarenes, pyrrolo[3,2-b]quinolines and pyrido[2,3-b]indoles, tethered to a biaryl system by a methyl-, ethyl- or propyl ether as PDE10A inhibitors. A number of analogues were prepared with variable chain length and evaluated for their ability to block PDE10A enzyme using a radiometric assay. Detailed SAR analyses revealed that compounds with an ethyl ether linker are superior in potency compared to compounds with methyl or propyl ether linkers. These compounds, in general, showed poor metabolic stability in rat and human liver microsomes. The metabolic profile of one of the potent compounds was studied in detail to identify metabolic liabilities of these compounds. Structural modifications were carried out that resulted in improved metabolic stability without significant loss of potency.
authors.affiliation: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India.
authors.forename: Sanjib
authors.initials: S
authors.lastname: Das
authors.affiliation: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India.
authors.forename: Rajendra L
authors.initials: RL
authors.lastname: Harde
authors.affiliation: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India.
authors.forename: Dnyaneshwar E
authors.initials: DE
authors.lastname: Shelke
authors.affiliation: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India.
authors.forename: Neelima
authors.initials: N
authors.lastname: Khairatkar-Joshi
authors.affiliation: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India.
authors.forename: Malini
authors.initials: M
authors.lastname: Bajpai
authors.affiliation: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India.
authors.forename: Ratika S
authors.initials: RS
authors.lastname: Sapalya
authors.affiliation: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India.
authors.forename: Harshada V
authors.initials: HV
authors.lastname: Surve
authors.affiliation: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India.
authors.forename: Girish S
authors.initials: GS
authors.lastname: Gudi
authors.affiliation: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India.
authors.forename: Rambabu
authors.initials: R
authors.lastname: Pattem
authors.affiliation: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India.
authors.forename: Dayanidhi B
authors.initials: DB
authors.lastname: Behera
authors.affiliation: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India.
authors.forename: Satyawan B
authors.initials: SB
authors.lastname: Jadhav
authors.affiliation: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India. Electronic address: abraham_thomas@glenmarkpharma.com.
authors.forename: Abraham
authors.initials: A
authors.lastname: Thomas
mesh_terms: D000818:Animals; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases
keywords: Met-ID studies; PDE10A inhibitors; Pyrido[2,3-b]indoles; Pyrrolo[3,2-b]quinolines