ABSTRACT
A systematic exploration of bioisosteric replacements for furan and thiophene cores in a series of potent A2BAR antagonists has been carried out using the nitrogen-walk approach. A collection of 42 novel alkyl 4-substituted-2-methyl-1,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxylates, which contain 18 different pentagonal heterocyclic frameworks at position 4, was synthesized and evaluated. This study enabled the identification of new ligands that combine remarkable affinity (Ki < 30 nM) and exquisite selectivity. The structure-activity relationship (SAR) trends identified were substantiated by a molecular modeling study, based on a receptor-driven docking model and including a systematic free energy perturbation (FEP) study. Preliminary evaluation of the CYP3A4 and CYP2D6 inhibitory activity in optimized ligands evidenced weak and negligible activity, respectively. The stereospecific interaction between hA2BAR and the eutomer of the most attractive novel antagonist (S)-18g (Ki = 3.66 nM) was validated.
Subject(s)
Adenosine A2 Receptor Antagonists/pharmacology , Imidazoles/pharmacology , Pyrimidines/pharmacology , Receptor, Adenosine A2B/metabolism , Adenosine A2 Receptor Antagonists/chemical synthesis , Adenosine A2 Receptor Antagonists/metabolism , Animals , CHO Cells , Cell Line, Tumor , Cricetulus , Cytochrome P-450 CYP2D6 Inhibitors/chemical synthesis , Cytochrome P-450 CYP2D6 Inhibitors/metabolism , Cytochrome P-450 CYP2D6 Inhibitors/pharmacology , Cytochrome P-450 CYP3A Inhibitors/chemical synthesis , Cytochrome P-450 CYP3A Inhibitors/metabolism , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Humans , Imidazoles/chemical synthesis , Imidazoles/metabolism , Molecular Docking Simulation , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Porcupine is an O-acyltransferase that regulates Wnt secretion. Inhibiting porcupine may block the Wnt pathway which is often dysregulated in various cancers. Consequently porcupine inhibitors are thought to be promising oncology therapeutics. A high throughput screen against porcupine revealed several potent hits that were confirmed to be Wnt pathway inhibitors in secondary assays. We developed a pharmacophore model and used the putative bioactive conformation of a xanthine inhibitor for scaffold hopping. The resulting maleimide scaffold was optimized to subnanomolar potency while retaining good physical druglike properties. A preclinical development candidate was selected for which extensive in vitro and in vivo profiling is reported.
Subject(s)
Acyltransferases/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Maleimides/pharmacology , Membrane Proteins/antagonists & inhibitors , Pyridazines/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Cytochrome P-450 CYP1A2 Inhibitors/administration & dosage , Cytochrome P-450 CYP1A2 Inhibitors/chemical synthesis , Cytochrome P-450 CYP1A2 Inhibitors/pharmacokinetics , Cytochrome P-450 CYP1A2 Inhibitors/pharmacology , Cytochrome P-450 CYP2D6 Inhibitors/administration & dosage , Cytochrome P-450 CYP2D6 Inhibitors/chemical synthesis , Cytochrome P-450 CYP2D6 Inhibitors/pharmacokinetics , Cytochrome P-450 CYP2D6 Inhibitors/pharmacology , Cytochrome P-450 CYP3A Inhibitors/administration & dosage , Cytochrome P-450 CYP3A Inhibitors/chemical synthesis , Cytochrome P-450 CYP3A Inhibitors/pharmacokinetics , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Female , HEK293 Cells , High-Throughput Screening Assays , Humans , Maleimides/administration & dosage , Maleimides/chemical synthesis , Maleimides/pharmacokinetics , Mice, Inbred BALB C , Mice, Nude , Microsomes, Liver/metabolism , Pyridazines/administration & dosage , Pyridazines/chemical synthesis , Pyridazines/pharmacokinetics , Rats , Structure-Activity Relationship , Wnt Signaling Pathway , Xenograft Model Antitumor AssaysABSTRACT
We report the discovery and hit-to-lead optimization of a structurally novel indazole series of CYP11B2 inhibitors. Benchmark compound 34 from this series displays potent inhibition of CYP11B2, high selectivity versus related steroidal and hepatic CYP targets, and lead-like physical and pharmacokinetic properties. On the basis of these and other data, the indazole series was progressed to lead optimization for further refinement.
Subject(s)
Antihypertensive Agents/pharmacology , Cytochrome P-450 CYP11B2/antagonists & inhibitors , Hypertension/drug therapy , Indazoles/pharmacology , Animals , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/pharmacokinetics , Aromatase Inhibitors/chemical synthesis , Aromatase Inhibitors/pharmacokinetics , Aromatase Inhibitors/pharmacology , Cell Line , Cricetulus , Cytochrome P-450 CYP2D6 Inhibitors/chemical synthesis , Cytochrome P-450 CYP2D6 Inhibitors/pharmacokinetics , Cytochrome P-450 CYP2D6 Inhibitors/pharmacology , Humans , Indazoles/chemical synthesis , Indazoles/pharmacokinetics , Macaca mulatta , Male , Rats, Sprague-Dawley , Stereoisomerism , Steroid 11-beta-Hydroxylase/antagonists & inhibitorsABSTRACT
We report the discovery of a novel benzylpiperidine derivative with serotonin transporter (SERT) inhibitory activity and 5-HT1A receptor weak partial agonistic activity showing the antidepressant-like effect. The 3-methoxyphenyl group and the phenethyl group of compound 1, which has weak SERT binding activity, but potent 5-HT1A binding activity, were optimized, leading to compound 35 with potent and balanced dual SERT and 5-HT1A binding activity, but also potent CYP2D6 inhibitory activity. Replacement of the methoxy group in the left part of compound 35 with a larger alkoxy group, such as ethoxy, isopropoxy or methoxy-ethoxy group ameliorated CYP2D6 inhibition, giving SMP-304 as a candidate. SMP-304 with serotonin uptake inhibitory activity and 5-HT1A weak partial agonistic activity, which could work as a 5-HT1A antagonist, displayed faster onset of antidepressant-like effect than a representative SSRI paroxetine in an animal model.
