title: Design, synthesis and pharmacological evaluation of novel polycyclic heteroarene ethers as PDE10A inhibitors: part II.
abstract: We report the design and synthesis of novel pyrrolo[3,2-b]quinoline containing heteroarene ethers as PDE10A inhibitors with good to excellent potency, selectivity and metabolic stability. Further optimization of this primary series resulted in the identification of 1-methyl-3-(4-{[3-(pyridine-4-yl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrolo[3,2-b]pyridine 13a with good hPDE10A potency (IC50: 6.3 nM), excellent selectivity over other related PDEs and desirable physicochemical properties. The compound exhibited high peripheral and adequate brain levels upon oral dosing in rodents. The compound also showed excellent efficacy in multiple preclinical animal models related to psychiatric disorders, particularly schizophrenia.
authors: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India.
authors: Sanjib
authors: S
authors: Das
authors: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India.
authors: Dnyaneshwar E
authors: DE
authors: Shelke
authors: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India.
authors: Rajendra L
authors: RL
authors: Harde
authors: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India.
authors: Vijayshree B
authors: VB
authors: Avhad
authors: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India.
authors: Neelima
authors: N
authors: Khairatkar-Joshi
authors: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India.
authors: Srinivas
authors: S
authors: Gullapalli
authors: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India.
authors: Praveen K
authors: PK
authors: Gupta
authors: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India.
authors: Maulik N
authors: MN
authors: Gandhi
authors: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India.
authors: Deepak K
authors: DK
authors: Bhateja
authors: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India.
authors: Malini
authors: M
authors: Bajpai
authors: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India.
authors: Ashwini A
authors: AA
authors: Joshi
authors: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India.
authors: Megha Y
authors: MY
authors: Marathe
authors: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India.
authors: Girish S
authors: GS
authors: Gudi
authors: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India.
authors: Satyawan B
authors: SB
authors: Jadhav
authors: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India.
authors: Mahamad Yunnus A
authors: MY
authors: Mahat
authors: Glenmark Research Centre, Glenmark Pharmaceuticals Ltd, MIDC, Mahape, Navi Mumbai 400 709, India. Electronic address: abraham_thomas@glenmarkpharma.com.
authors: Abraham
authors: A
authors: Thomas
mesh_terms: D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004987:Ethers / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000882:Haplorhini; D006801:Humans; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011719:Pyrazines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: C000595733:1-methyl-3-(4-((3-(pyridine-4-yl)pyrazin-2-yl)oxy)phenyl)-1H-pyrrolo(3,2-b)pyridine; D004987:Ethers; D010726:Phosphodiesterase Inhibitors; D011719:Pyrazines; D011725:Pyridines; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases
keywords: CAR model in SD rats; PPI deficit model; Pyrrolo[3,2-b]pyridine; Pyrrolo[3,2-b]quinoline; Sniffing versus climbing in mice