ABSTRACT
Endogenous nitrosothiols (SNOs) including S-nitrosoglutathione (GSNO) serve as reservoir for bioavailable nitric oxide (NO) and mediate NO-based signaling, inflammatory status and smooth muscle function in the lung. GSNOR inhibition increases pulmonary GSNO and induces bronchodilation while reducing inflammation in lung diseases. In this letter, design, synthesis and structure-activity relationships (SAR) of novel imidazole-biaryl-tetrazole based GSNOR inhibitors are described. Many potent inhibitors (30, 39, 41, 42, 44, 45 and 58) were identified with low nanomolar activity (IC50s: <15â¯nM) along with adequate metabolic stability. Lead compounds 30 and 58 exhibited good exposure and oral bioavailability in mouse pharmacokinetic (PK) study. Compound 30 was selected for further profiling and revealed comparable mouse and rat GSNOR potency, high selectivity against alcohol dehydrogenase (ADH) and carbonyl reductase (CBR1) family of enzymes, low efflux ratio and permeability in PAMPA, a high permeability in CALU-3 assay, significantly low hERG activity and minimal off-target activity. Further, an in vivo efficacy of compound 30 is disclosed in cigarette smoke (CS) induced mouse model for COPD.
Subject(s)
Aldehyde Oxidoreductases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Imidazoles/chemistry , Imidazoles/pharmacology , Pulmonary Disease, Chronic Obstructive/drug therapy , Tetrazoles/chemistry , Tetrazoles/pharmacology , Administration, Oral , Aldehyde Oxidoreductases/metabolism , Animals , Cigarette Smoking/adverse effects , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacokinetics , Halogenation , Humans , Imidazoles/administration & dosage , Imidazoles/pharmacokinetics , Male , Mice , Mice, Inbred C57BL , Pulmonary Disease, Chronic Obstructive/etiology , Pulmonary Disease, Chronic Obstructive/metabolism , Structure-Activity Relationship , Tetrazoles/administration & dosage , Tetrazoles/pharmacokineticsABSTRACT
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.
Subject(s)
Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/drug effects , Pyridones/chemical synthesis , Pyridones/pharmacology , Acetates/chemical synthesis , Acetates/pharmacokinetics , Animals , Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/pharmacology , Area Under Curve , Dogs , Drug Design , Female , Glucuronides/metabolism , Macaca fascicularis , Male , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Phosphodiesterase Inhibitors/pharmacokinetics , Prodrugs , Psychoses, Substance-Induced/drug therapy , Pyridones/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
The transient receptor potential canonical (TRPC) channels have gained interest as potential therapeutic targets for respiratory diseases, neurological disorders, cardiovascular disorders, pain, cancer and several other pathological conditions. The TRPC receptor family consists of seven isoforms (C1-C7) and has been divided into three subfamilies based on structural and functional similarities. Several pharmaceutical companies and academic institutes are currently exploring the potential of these nonselective cation channels as therapeutic targets using small molecule inhibitors or modulators. This review covers patents on TRPC receptor modulators published from 2002 to 2014. The review mainly focuses on TRPC receptor target biology, small and large molecule modulators and their therapeutic potential.