ABSTRACT
Several novel N-type voltage sensitive calcium channel blockers showed high affinity in the IMR32 assay and efficacy in the anti-writhing model. Herein, we describe the design, synthesis, SAR studies, biological data, physicochemical properties and pharmacokinetics of this 4-piperidinylaniline series.
Subject(s)
Analgesics, Non-Narcotic/pharmacology , Aniline Compounds/pharmacology , Calcium Channel Blockers/pharmacology , Calcium Channels, N-Type/drug effects , Animals , Calcium Channel Blockers/chemical synthesis , Mice , Structure-Activity RelationshipABSTRACT
Our drug discovery efforts for N-type calcium channel blockers in the 4-piperidinylaniline series led to the discovery of an orally active analgesic agent 26.1-[4-Dimethylamino-benzyl)-piperidin-4-yl]-[4-(3,3-dimethyl-but yl)-phenyl]-(3-methyl-but-2-enyl)amine (26) showed high affinity to functionally block N-type calcium channels (IC50=0.7 microM in the IMR32 assay) and exhibited high efficacy in the anti-writhing analgesia test with mice (ED50=12 mg/kg by po and 4 mg/kg by iv). In this report, the rationale for the design, synthesis, biological evaluation, and pharmacokinetics of this series of blockers is described.
Subject(s)
Analgesics/chemistry , Analgesics/pharmacology , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Calcium Channel Blockers/chemistry , Calcium Channel Blockers/pharmacology , Calcium Channels, N-Type/drug effects , Piperidines/chemistry , Piperidines/pharmacology , Administration, Oral , Analgesics/chemical synthesis , Aniline Compounds/chemical synthesis , Animals , Calcium Channel Blockers/administration & dosage , Calcium Channel Blockers/chemical synthesis , Cell Line , Magnetic Resonance Spectroscopy , Male , Mass Spectrometry , Mice , Molecular Structure , Piperidines/chemical synthesis , Rats , Rats, WistarABSTRACT
Exploration of the SAR around the leucine side chain in a series of N,N-dialkyldipeptidylamines with potent functional activity at N-type VSCC is presented. A novel analog is disclosed which possesses improved aqueous solubility, in vivo activity in an audiogenic seizure model, and reversible blockade in electrophysiological assays.
Subject(s)
Alkanes/chemistry , Calcium Channel Blockers/chemistry , Calcium Channels, N-Type/metabolism , Leucine/chemistry , Oligopeptides/chemistry , Alkanes/chemical synthesis , Alkanes/pharmacology , Calcium Channel Blockers/chemical synthesis , Calcium Channel Blockers/pharmacology , Calcium Channels, N-Type/drug effects , Dipeptides/chemical synthesis , Dipeptides/chemistry , Dipeptides/pharmacology , Electrophysiology , Oligopeptides/chemical synthesis , Oligopeptides/pharmacology , Solubility , Structure-Activity Relationship , omega-Conotoxins/chemical synthesis , omega-Conotoxins/chemistry , omega-Conotoxins/pharmacologyABSTRACT
In this article, the rationale for the design, synthesis, and biological evaluation of a series of N-type voltage-sensitive calcium channel (VSCC) blockers is described. N-Type VSCC blockers, such as ziconotide, have shown utility in several models of stroke and pain. Modification of the previously reported lead, 1a, led to several 4-(4-benzyloxylphenyl)piperidine structures with potent in vitro and in vivo activities. In this series, the most interesting compound, (S)-2-amino-1-{4-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-p iperidin-1-yl}-4-methyl-pentan-1-one (11), blocked N-type calcium channels (IC(50) = 0.67 microM in the IMR32 assay) and was efficacious in the audiogenic DBA/2 seizure mouse model (ED(50) = 6 mg/kg, iv) as well as the antiwrithing model (ED(50) = 6 mg/kg, iv). Whole-cell voltage-clamp electrophysiology experiments demonstrated that compound 11 blocked N-type Ca(2+) channels and Na(+) channels in superior cervical ganglion neurons at similar concentrations. Compound 11, which showed superior in vivo efficacy, stands out as an interesting lead for further development of neurotherapeutic agents in this series.
Subject(s)
Analgesics, Non-Narcotic/chemical synthesis , Anticonvulsants/chemical synthesis , Calcium Channel Blockers/chemical synthesis , Neurons/metabolism , Piperidines/chemical synthesis , Acoustic Stimulation , Analgesics, Non-Narcotic/chemistry , Analgesics, Non-Narcotic/pharmacokinetics , Analgesics, Non-Narcotic/pharmacology , Animals , Anticonvulsants/chemistry , Anticonvulsants/pharmacokinetics , Anticonvulsants/pharmacology , Blood Pressure/drug effects , Calcium Channel Blockers/chemistry , Calcium Channel Blockers/pharmacokinetics , Calcium Channel Blockers/pharmacology , Cell Line , Heart Rate/drug effects , Humans , In Vitro Techniques , Ion Channel Gating , Male , Mice , Mice, Inbred DBA , Microsomes, Liver/metabolism , Pain Measurement , Patch-Clamp Techniques , Piperidines/chemistry , Piperidines/pharmacokinetics , Piperidines/pharmacology , Rats , Rats, Sprague-Dawley , Rats, Wistar , Seizures/drug therapyABSTRACT
Selective N-Type Voltage Sensitive Calcium Channel (VSCC) antagonists have shown utility in several models of pain and ischemia. We report the structure-activity relationship at the proximal phenyl group in a series of non-peptidyl VSCC blockers.
Subject(s)
Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Calcium Channel Blockers/chemistry , Calcium Channel Blockers/pharmacology , Leucine/analogs & derivatives , Acoustic Stimulation , Amino Acid Sequence , Aniline Compounds/therapeutic use , Animals , Calcium Channel Blockers/therapeutic use , Leucine/chemistry , Leucine/pharmacology , Leucine/therapeutic use , Mice , Mice, Inbred DBA , Molecular Sequence Data , Seizures/drug therapy , Seizures/physiopathology , Structure-Activity RelationshipABSTRACT
Selective N-type voltage sensitive calcium channel (VSCC) blockers have shown efficacy in several animal models of stroke and pain. In the process of searching for small molecule N-type calcium channel blockers, we have identified a series of N-methyl-N-aralkyl-peptidylamines with potent functional activity at N-type VSCCs. The most active compound discovered in this series is PD 173212 (11, IC50 = 36 nM in the IMR-32 assays). SAR and pharmacological evaluation of this series are described.
Subject(s)
Calcium Channel Blockers/pharmacology , Calcium Channels/metabolism , Dipeptides/pharmacology , Animals , Calcium Channel Blockers/therapeutic use , Calcium Channels/drug effects , Dipeptides/chemistry , Disease Models, Animal , Humans , Mice , Seizures/drug therapy , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Selective N-type Voltage Sensitive Calcium Channel (VSCC) blockers have shown utility in several models of stroke and pain. A series of N,N-dialkyldipeptidylamines with potent functional activity at N-type VSCC's has been identified. Multiple parallel synthesis of a focused array of thirty compounds using polymer-supported quenching reagents and preliminary pharmacology are presented. Eighteen compounds were identified with an IC50 below 1 microM in an in vitro functional assay.
Subject(s)
Amines/chemical synthesis , Calcium Channel Blockers/chemical synthesis , Dipeptides/chemical synthesis , Inhibitory Concentration 50ABSTRACT
Selective N-type Voltage Activated Calcium Channel (VACC) blockers have shown utility in several models of stroke and pain. In the process of searching for small molecules as N-type calcium channel blockers, we have identified a series of N,N-dialkylpeptidylamines (e.g., PD 175069) with potent functional activity at N-type VACC. Further modification of the leucine moiety of PD 175069 with a cyclized ring structure provides a series of novel molecules. Syntheses and pharmacological evaluation of the series are presented.
Subject(s)
Calcium Channel Blockers/chemical synthesis , Calcium Channel Blockers/pharmacokinetics , Phenylalanine/analogs & derivatives , Phenylalanine/chemical synthesis , Phenylalanine/pharmacokinetics , Humans , Inhibitory Concentration 50 , Models, Chemical , Tumor Cells, CulturedABSTRACT
Selective N-type voltage sensitive calcium channel (VSCC) blockers have shown utility in several models of stroke and pain. We are especially interested in small molecule N-type calcium channel blockers for therapeutic use. Herein, we report a series of N,N-dialkyl-dipeptidylamines with potent functional activity at N-type VSCCs and in vivo efficacy. The synthesis, SAR, and pharmacological evaluation of this series are discussed.
Subject(s)
Calcium Channel Blockers/chemical synthesis , Diamines/chemical synthesis , Diamines/pharmacology , Dipeptides/chemical synthesis , Dipeptides/pharmacology , Animals , Disease Models, Animal , Mice , Mice, Inbred DBA , Models, Chemical , Seizures/drug therapyABSTRACT
Optimization of a 2-step reaction sequence was accomplished in 3-4 days, with over 200 different reaction conditions evaluated. Combinatorial arrays were performed using the optimized conditions to synthesize 590 new compounds which were tested for inhibition against N-His (D381E) ICE. Thirty-five compounds showed at least a tenfold improvement in activity compared to an initial standard.