title: Design, Synthesis, and Pharmacological Evaluation of 5,6-Disubstituted Pyridin-2(1H)-one Derivatives as Phosphodiesterase 10A (PDE10A) Antagonists.
abstract: We report the design and synthesis of novel 5,6-diarylated pyridin-2(1H)-one derivatives as pharmacophoric PDE10A inhibitors. This highly potent molecular scaffold was developed from an inactive diarylpyridine-2-amine derivative 3b by extensive and systematic analogue synthesis and SAR analysis. Further optimization of the scaffold resulted in identification of pyridin-2(1H)-one 18b as a lead compound with good potency (IC50 = 1.6 nM) and selectivity (>6000-fold) over other related PDEs but with a poor pharmacokinetic profile. Careful metabolite profiling of 18b revealed that poor systemic exposure in rats (Cmax = 44 ng/mL; AUC0-t = 359 ng · h/mL) at 10 mg/kg was due to the formation of O-glucuronide conjugate by phase 2 metabolism. The structure of the glucuronide metabolite was confirmed by retention time and LC-MS/MS fragmentation matching with the synthetic glucuronide 26. The problem of low exposure of 18b was effectively addressed by its conversion to an acetate prodrug 25b, which upon oral dosing resulted in an improved pharmacokinetic profile (Cmax = 359 ng.h/mL; AUC0-t = 2436 ng.h/mL) and a desirable brain to plasma ratio of 1.2. The prodrug 25b showed good efficacy in selected rodent models of psychosis.
authors.affiliation: Medicinal Chemistry Division, ‡Pharmacology Division, and §Drug Metabolism and Pharmacokinetics, Glenmark Research Centre , A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai, 400 709, India.
authors.forename: V S Prasadarao
authors.initials: VS
authors.lastname: Lingam
authors.affiliation: Medicinal Chemistry Division, ‡Pharmacology Division, and §Drug Metabolism and Pharmacokinetics, Glenmark Research Centre , A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai, 400 709, India.
authors.forename: Dnyaneshwar H
authors.initials: DH
authors.lastname: Dahale
authors.affiliation: Medicinal Chemistry Division, ‡Pharmacology Division, and §Drug Metabolism and Pharmacokinetics, Glenmark Research Centre , A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai, 400 709, India.
authors.forename: Vijay E
authors.initials: VE
authors.lastname: Rathi
authors.affiliation: Medicinal Chemistry Division, ‡Pharmacology Division, and §Drug Metabolism and Pharmacokinetics, Glenmark Research Centre , A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai, 400 709, India.
authors.forename: Yogesh B
authors.initials: YB
authors.lastname: Shingote
authors.affiliation: Medicinal Chemistry Division, ‡Pharmacology Division, and §Drug Metabolism and Pharmacokinetics, Glenmark Research Centre , A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai, 400 709, India.
authors.forename: Rajni R
authors.initials: RR
authors.lastname: Thakur
authors.affiliation: Medicinal Chemistry Division, ‡Pharmacology Division, and §Drug Metabolism and Pharmacokinetics, Glenmark Research Centre , A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai, 400 709, India.
authors.forename: Ajit S
authors.initials: AS
authors.lastname: Mindhe
authors.affiliation: Medicinal Chemistry Division, ‡Pharmacology Division, and §Drug Metabolism and Pharmacokinetics, Glenmark Research Centre , A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai, 400 709, India.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Kummari
authors.affiliation: Medicinal Chemistry Division, ‡Pharmacology Division, and §Drug Metabolism and Pharmacokinetics, Glenmark Research Centre , A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai, 400 709, India.
authors.forename: Neelima
authors.initials: N
authors.lastname: Khairatkar-Joshi
authors.affiliation: Medicinal Chemistry Division, ‡Pharmacology Division, and §Drug Metabolism and Pharmacokinetics, Glenmark Research Centre , A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai, 400 709, India.
authors.forename: Malini
authors.initials: M
authors.lastname: Bajpai
authors.affiliation: Medicinal Chemistry Division, ‡Pharmacology Division, and §Drug Metabolism and Pharmacokinetics, Glenmark Research Centre , A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai, 400 709, India.
authors.forename: Daisy M
authors.initials: DM
authors.lastname: Shah
authors.affiliation: Medicinal Chemistry Division, ‡Pharmacology Division, and §Drug Metabolism and Pharmacokinetics, Glenmark Research Centre , A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai, 400 709, India.
authors.forename: Ratika S
authors.initials: RS
authors.lastname: Sapalya
authors.affiliation: Medicinal Chemistry Division, ‡Pharmacology Division, and §Drug Metabolism and Pharmacokinetics, Glenmark Research Centre , A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai, 400 709, India.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Gullapalli
authors.affiliation: Medicinal Chemistry Division, ‡Pharmacology Division, and §Drug Metabolism and Pharmacokinetics, Glenmark Research Centre , A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai, 400 709, India.
authors.forename: Praveen K
authors.initials: PK
authors.lastname: Gupta
authors.affiliation: Medicinal Chemistry Division, ‡Pharmacology Division, and §Drug Metabolism and Pharmacokinetics, Glenmark Research Centre , A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai, 400 709, India.
authors.forename: Girish S
authors.initials: GS
authors.lastname: Gudi
authors.affiliation: Medicinal Chemistry Division, ‡Pharmacology Division, and §Drug Metabolism and Pharmacokinetics, Glenmark Research Centre , A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai, 400 709, India.
authors.forename: Satyawan B
authors.initials: SB
authors.lastname: Jadhav
authors.affiliation: Medicinal Chemistry Division, ‡Pharmacology Division, and §Drug Metabolism and Pharmacokinetics, Glenmark Research Centre , A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai, 400 709, India.
authors.forename: Rambabu
authors.initials: R
authors.lastname: Pattem
authors.affiliation: Medicinal Chemistry Division, ‡Pharmacology Division, and §Drug Metabolism and Pharmacokinetics, Glenmark Research Centre , A-607, TTC Industrial Area, MIDC Mahape, Navi Mumbai, 400 709, India.
authors.forename: Abraham
authors.initials: A
authors.lastname: Thomas
mesh_terms: D000085:Acetates / Q000138:chemical synthesis / Q000493:pharmacokinetics; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D019540:Area Under Curve; D004285:Dogs; D015195:Drug Design; D005260:Female; D020719:Glucuronides / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects*; D011355:Prodrugs; D011605:Psychoses, Substance-Induced / Q000188:drug therapy; D011728:Pyridones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D000085:Acetates; D014150:Antipsychotic Agents; D020719:Glucuronides; D010726:Phosphodiesterase Inhibitors; D011355:Prodrugs; D011728:Pyridones; C512064:PDE10A protein, rat; D010727:Phosphoric Diester Hydrolases