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1.
J Org Chem ; 81(23): 12060-12064, 2016 12 02.
Article in English | MEDLINE | ID: mdl-27934457

ABSTRACT

An efficient asymmetric synthesis of dipyridyl TRPV3 antagonist 1 is reported. The four-step route involves two C-C bond-forming steps, a highly diastereoselective alkene hydration, and asymmetric ketone hydrosilylation in 97% ee.


Subject(s)
TRPV Cation Channels/antagonists & inhibitors , Carbon-13 Magnetic Resonance Spectroscopy , Humans , Proton Magnetic Resonance Spectroscopy , Pyridines/chemistry , Spectrometry, Mass, Electrospray Ionization , Stereoisomerism
2.
J Med Chem ; 59(10): 4926-47, 2016 05 26.
Article in English | MEDLINE | ID: mdl-27077528

ABSTRACT

Transient receptor potential vanilloid 3 (TRPV3) is a Ca(2+)- and Na(+)-permeable channel with a unique expression pattern. TRPV3 is found in both neuronal and non-neuronal tissues, including dorsal root ganglia, spinal cord, and keratinocytes. Recent studies suggest that TRPV3 may play a role in inflammation, pain sensation, and skin disorders. TRPV3 studies have been challenging, in part due to a lack of research tools such as selective antagonists. Herein, we provide the first detailed report on the development of potent and selective TRPV3 antagonists featuring a pyridinyl methanol moiety. Systematic optimization of pharmacological, physicochemical, and ADME properties of original lead 5a resulted in identification of a novel and selective TRPV3 antagonist 74a, which demonstrated a favorable preclinical profile in two different models of neuropathic pain as well as in a reserpine model of central pain.


Subject(s)
Cyclobutanes/chemical synthesis , Cyclobutanes/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , TRPV Cation Channels/antagonists & inhibitors , Calcium/metabolism , Cyclobutanes/chemistry , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Molecular Conformation , Pyridines/chemistry , Structure-Activity Relationship , TRPV Cation Channels/metabolism
3.
J Med Chem ; 59(7): 3373-91, 2016 Apr 14.
Article in English | MEDLINE | ID: mdl-27015369

ABSTRACT

The genetic validation for the role of the Nav1.7 voltage-gated ion channel in pain signaling pathways makes it an appealing target for the potential development of new pain drugs. The utility of nonselective Nav blockers is often limited due to adverse cardiovascular and CNS side effects. We sought more selective Nav1.7 blockers with oral activity, improved selectivity, and good druglike properties. The work described herein focused on a series of 3- and 4-substituted indazoles. SAR studies of 3-substituted indazoles yielded analog 7 which demonstrated good in vitro and in vivo activity but poor rat pharmacokinetics. Optimization of 4-substituted indazoles yielded two compounds, 27 and 48, that exhibited good in vitro and in vivo activity with improved rat pharmacokinetic profiles. Both 27 and 48 demonstrated robust activity in the acute rat monoiodoacetate-induced osteoarthritis model of pain, and subchronic dosing of 48 showed a shift to a lower EC50 over 7 days.


Subject(s)
Analgesics/pharmacology , Imidazolidines/pharmacology , Indazoles/pharmacology , NAV1.7 Voltage-Gated Sodium Channel/chemistry , Osteoarthritis/drug therapy , Pain/drug therapy , Pyrroles/pharmacology , Sodium Channel Blockers/pharmacology , Analgesics/chemistry , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Electrophysiology , Evoked Potentials , Imidazolidines/chemistry , Indazoles/chemistry , Iodoacetic Acid/toxicity , Molecular Structure , NAV1.7 Voltage-Gated Sodium Channel/metabolism , Osteoarthritis/chemically induced , Osteoarthritis/metabolism , Pain/metabolism , Pain/pathology , Pain Measurement , Pyrroles/chemistry , Rats , Sodium Channel Blockers/chemistry , Structure-Activity Relationship
4.
Temperature (Austin) ; 2(2): 297-301, 2015.
Article in English | MEDLINE | ID: mdl-27227030

ABSTRACT

Transient receptor potential vanilloid 1 (TRPV1) is a multifunctional ion channel playing important roles in a numerous biological processes including the regulation of body temperature. Within distinct and tight chemical space of chromanyl ureas TRPV1 ligands were identified that exhibit distinctive pharmacology and a spectrum of thermoregulatory effects ranging from hypothermia to hyperthermia. The ability to manipulate these effects by subtle structural modifications of chromanyl ureas may serve as a productive approach in TRPV1 drug discovery programs addressing either side effect or desired target profiles of the compounds. Because chromanyl ureas in the TRPV1 context are generally antagonists, we verified observed partial agonist effects of a subset of compounds within that chemotype by comparing the in vitro profile of Compound 3 with known partial agonist 5'-I-RTX.

5.
J Med Chem ; 57(17): 7412-24, 2014 Sep 11.
Article in English | MEDLINE | ID: mdl-25100568

ABSTRACT

The synthesis and characterization of a series of selective, orally bioavailable 1-(chroman-4-yl)urea TRPV1 antagonists is described. Whereas first-generation antagonists that inhibit all modes of TRPV1 activation can elicit hyperthermia, the compounds disclosed herein do not elevate core body temperature in preclinical models and only partially block acid activation of TRPV1. Advancing the SAR of this series led to the eventual identification of (R)-1-(7-chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea (A-1165442, 52), an analogue that possesses excellent pharmacological selectivity, has a favorable pharmacokinetic profile, and demonstrates good efficacy against osteoarthritis pain in rodents.


Subject(s)
Analgesics/chemistry , Body Temperature/drug effects , TRPV Cation Channels/antagonists & inhibitors , Urea/chemistry , Analgesics/pharmacokinetics , Analgesics/pharmacology , Animals , Area Under Curve , Body Temperature/physiology , Dogs , Dose-Response Relationship, Drug , Drug Discovery , HEK293 Cells , Humans , Isoquinolines/chemistry , Isoquinolines/pharmacokinetics , Isoquinolines/pharmacology , Metabolic Clearance Rate , Models, Chemical , Molecular Structure , Rats , Structure-Activity Relationship , TRPV Cation Channels/chemistry , TRPV Cation Channels/metabolism , Urea/analogs & derivatives , Urea/pharmacokinetics , Urea/pharmacology
6.
J Pharmacol Exp Ther ; 342(2): 416-28, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22570364

ABSTRACT

The transient receptor potential vanilloid-1 (TRPV1) channel is involved in the development and maintenance of pain and participates in the regulation of temperature. The channel is activated by diverse agents, including capsaicin, noxious heat (≥ 43°C), acidic pH (< 6), and endogenous lipids including N-arachidonoyl dopamine (NADA). Antagonists that block all modes of TRPV1 activation elicit hyperthermia. To identify efficacious TRPV1 antagonists that do not affect temperature antagonists representing multiple TRPV1 pharmacophores were evaluated at recombinant rat and human TRPV1 channels with Ca(2+) flux assays, and two classes of antagonists were identified based on their differential ability to inhibit acid activation. Although both classes of antagonists completely blocked capsaicin- and NADA-induced activation of TRPV1, select compounds only partially inhibited activation of the channel by protons. Electrophysiology and calcitonin gene-related peptide release studies confirmed the differential pharmacology of these antagonists at native TRPV1 channels in the rat. Comparison of the in vitro pharmacological properties of these TRPV1 antagonists with their in vivo effects on core body temperature confirms and expands earlier observations that acid-sparing TRPV1 antagonists do not significantly increase core body temperature. Although both classes of compounds elicit equivalent analgesia in a rat model of knee joint pain, the acid-sparing antagonist tested is not effective in a mouse model of bone cancer pain.


Subject(s)
Body Temperature/drug effects , TRPV Cation Channels/antagonists & inhibitors , Analgesics/pharmacology , Animals , Calcitonin Gene-Related Peptide/metabolism , Calcium/metabolism , Capsaicin/pharmacology , Cell Line, Transformed , Fever/drug therapy , Fever/physiopathology , HEK293 Cells , Humans , Male , Mice , Mice, Inbred C3H , Neurons/drug effects , Neurons/metabolism , Pain/drug therapy , Pain/metabolism , Pain/physiopathology , Protons , Rats , Rats, Sprague-Dawley , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , TRPV Cation Channels/metabolism
7.
Blood Coagul Fibrinolysis ; 23(1): 94-7, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22089942

ABSTRACT

Capsaicin is an agonist of transient receptor potential vanilloid type 1 (TRPV1), in which it can act as a neuronal stimulant and result in nociception. Capsaicin also affects a variety of nonneuronal tissues, in which its mechanisms of action are less certain. The present study investigated whether the inhibitory effects of capsaicin on platelet aggregation are mediated via TRPV1. Venous whole blood obtained from beagle dogs (n = 6) was preincubated with capsaicin and/or the potent and selective competitive TRPV1 antagonist, A-993610 and then exposed to collagen (2 µg/ml). An aggregometer was used to quantify the platelet response. Capsaicin exposure inhibited collagen-induced platelet aggregation in a concentration-dependent manner, with significant effects at 10 and 30 µg capsaicin per millilitre. A-993610 alone (0.1-1.0 µg/ml) had no effects on collagen-induced platelet aggregation, nor did it have any effects on capsaicin's ability to inhibit platelet aggregation. The current results agree with previous findings that capsaicin can inhibit platelet aggregation. In addition, the present study demonstrates that capsaicin's inhibitory effect on collagen-induced canine platelet aggregation is not mediated by TRPV1.


Subject(s)
Capsaicin/pharmacology , Platelet Aggregation/drug effects , TRPV Cation Channels/metabolism , Animals , Dogs , Male , TRPV Cation Channels/agonists , TRPV Cation Channels/antagonists & inhibitors
8.
Bioorg Med Chem Lett ; 21(5): 1338-41, 2011 Mar 01.
Article in English | MEDLINE | ID: mdl-21315587

ABSTRACT

Novel chroman and tetrahydroquinoline ureas were synthesized and evaluated for their activity as TRPV1 antagonists. It was found that aryl substituents on the 7- or 8-position of both bicyclic scaffolds imparted the best in vitro potency at TRPV1. The most potent chroman ureas were assessed in chronic and acute pain models, and compounds with the ability to cross the blood-brain barrier were shown to be highly efficacious. The tetrahydroquinoline ureas were found to be potent CYP3A4 inhibitors, but replacement of bulky substituents at the nitrogen atom of the tetrahydroisoquinoline moiety with small groups such as methyl can minimize the inhibition.


Subject(s)
Chromans , Quinolines , TRPV Cation Channels/antagonists & inhibitors , Urea/pharmacology , Chromans/chemical synthesis , Chromans/chemistry , Chromans/pharmacology , Humans , Inhibitory Concentration 50 , Molecular Structure , Quinolines/chemistry , Urea/chemical synthesis , Urea/chemistry
9.
J Org Chem ; 75(24): 8713-5, 2010 Dec 17.
Article in English | MEDLINE | ID: mdl-21090730

ABSTRACT

An efficient synthesis of 2-amino-oxazolo[4,5-c]quinoline TRPV1 antagonists is described via a thiourea formation/carbodiimide cyclization sequence. Synthetic route optimization eliminates intermediate isolations and facilitates the rapid preparation of a series of novel pentacyclic TRPV1 antagonists. From this series, compound (S)-4 was identified as a potent and selective ligand for the TRPV1 ion channel.


Subject(s)
Heterocyclic Compounds/chemical synthesis , Oxazoles/chemical synthesis , Quinolines/chemical synthesis , TRPV Cation Channels/antagonists & inhibitors , Thiourea/chemical synthesis , Capsaicin/chemistry , Crystallography, X-Ray , Heterocyclic Compounds/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , Oxazoles/chemistry , Quinolines/chemistry , Structure-Activity Relationship , TRPV Cation Channels/chemistry , Thiourea/chemistry
10.
Pain ; 142(1-2): 27-35, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19135797

ABSTRACT

Transient receptor potential vanilloid type 1 (TRPV1) is a ligand-gated ion channel that functions as an integrator of multiple pain stimuli including heat, acid, capsaicin and a variety of putative endogenous lipid ligands. TRPV1 antagonists have been shown to decrease inflammatory pain in animal models and to produce limited hyperthermia at analgesic doses. Here, we report that ABT-102, which is a potent and selective TRPV1 antagonist, is effective in blocking nociception in rodent models of inflammatory, post-operative, osteoarthritic, and bone cancer pain. ABT-102 decreased both spontaneous pain behaviors and those evoked by thermal and mechanical stimuli in these models. Moreover, we have found that repeated administration of ABT-102 for 5-12 days increased its analgesic activity in models of post-operative, osteoarthritic, and bone cancer pain without an associated accumulation of ABT-102 concentration in plasma or brain. Similar effects were also observed with a structurally distinct TRPV1 antagonist, A-993610. Although a single dose of ABT-102 produced a self-limiting increase in core body temperature that remained in the normal range, the hyperthermic effects of ABT-102 effectively tolerated following twice-daily dosing for 2 days. Therefore, the present data demonstrate that, following repeated administration, the analgesic activity of TRPV1 receptor antagonists is enhanced, while the associated hyperthermic effects are attenuated. The analgesic efficacy of ABT-102 supports its advancement into clinical studies.


Subject(s)
Analgesics/administration & dosage , Fever/drug therapy , Indazoles/administration & dosage , Pain Threshold/drug effects , Pain/drug therapy , TRPV Cation Channels/metabolism , Urea/analogs & derivatives , Animals , Body Temperature/drug effects , Bone Neoplasms/complications , Calcium/metabolism , Disease Models, Animal , Drug Interactions , Fever/chemically induced , Inflammation/complications , Male , Mice , Mice, Inbred C3H , Motor Activity/drug effects , Osteoarthritis/complications , Pain/etiology , Pain Measurement , Rats , Rats, Sprague-Dawley , TRPV Cation Channels/antagonists & inhibitors , Urea/administration & dosage
11.
J Med Chem ; 50(15): 3627-44, 2007 Jul 26.
Article in English | MEDLINE | ID: mdl-17585748

ABSTRACT

A series of exceptionally potent agonists at neuronal nicotinic acetylcholine receptors (nAChRs) has been investigated. Several N-(3-pyridinyl) derivatives of bridged bicyclic diamines exhibit double-digit-picomolar binding affinities for the alpha 4 beta 2 subtype, placing them with epibatidine among the most potent nAChR ligands described to date. Structure-activity studies have revealed that substitutions, particularly hydrophilic groups in the pyridine 5-position, differentially modulate the agonist activity at ganglionic vs central nAChR subtypes, so that improved subtype selectivity can be demonstrated in vitro. Analgesic efficacy has been achieved across a broad range of pain states, including rodent models of acute thermal nociception, persistent pain, and neuropathic allodynia. Unfortunately, the hydrophilic pyridine substituents that were shown to enhance agonist selectivity for central nAChRs in vitro tend to limit CNS penetration in vivo, so that analgesic efficacy with an improved therapeutic window was not realized with those compounds.


Subject(s)
Analgesics/chemical synthesis , Diamines/chemical synthesis , Heterocyclic Compounds, Bridged-Ring/chemical synthesis , Nicotinic Agonists/chemical synthesis , Pyridines/chemical synthesis , Analgesics/chemistry , Analgesics/pharmacology , Animals , Binding, Competitive , Brain/drug effects , Brain/metabolism , Cell Line , Diamines/chemistry , Diamines/pharmacology , Dopamine/metabolism , Heterocyclic Compounds, Bridged-Ring/chemistry , Heterocyclic Compounds, Bridged-Ring/pharmacology , In Vitro Techniques , Ligands , Models, Molecular , Nicotinic Agonists/chemistry , Nicotinic Agonists/pharmacology , Pain/drug therapy , Pain/etiology , Pain Measurement , Peripheral Nervous System Diseases/drug therapy , Pyridines/chemistry , Pyridines/pharmacology , Rats , Receptors, Nicotinic/metabolism , Stereoisomerism , Structure-Activity Relationship
12.
J Med Chem ; 49(26): 7843-53, 2006 Dec 28.
Article in English | MEDLINE | ID: mdl-17181167

ABSTRACT

A series of potent neuronal nicotinic acetylcholine receptor (nAChR) ligands based on a 3,8-diazabicyclo[4.2.0]octane core have been synthesized and evaluated for affinity and agonist efficacy at the human high affinity nicotine recognition site (halpha4beta2) and in a rat model of persistent nociceptive pain (formalin model). Numerous analogs in this series exhibit picomolar affinity in radioligand binding assays and nanomolar agonist potency in functional assays, placing them among the most potent nAChR ligands known for the halpha4beta2 receptor. Several of the compounds reported in this study (i.e., 24, 25, 28, 30, 32, and 47) exhibit equivalent or greater affinity for the halpha4beta2 receptor relative to epibatidine, and like epibatidine, many exhibit robust analgesic efficacy in the rat formalin model of persistent pain.


Subject(s)
Analgesics/metabolism , Nicotinic Agonists/chemical synthesis , Octanes/chemical synthesis , Pain/drug therapy , Receptors, Nicotinic/metabolism , Analgesics/chemical synthesis , Analgesics/chemistry , Animals , Binding, Competitive , Bridged Bicyclo Compounds, Heterocyclic/metabolism , Calcium/metabolism , Humans , Ligands , Molecular Conformation , Molecular Structure , Nicotinic Agonists/chemistry , Nicotinic Agonists/metabolism , Octanes/chemistry , Octanes/metabolism , Pyridines/metabolism , Radioligand Assay , Rats , Receptors, Nicotinic/chemistry , Structure-Activity Relationship
13.
J Org Chem ; 71(22): 8378-83, 2006 Oct 27.
Article in English | MEDLINE | ID: mdl-17064008

ABSTRACT

A gram scale synthesis of the glucuronide metabolite of ABT-724 is reported. Glycosidic coupling between a trichloroacetimidate glucuronyl donor and a Cbz-protected hydroxypyridylpiperazine glycosyl acceptor is the key step in the synthesis, since attempts to directly glucuronidate the aglycon, aglycon derivatives, and other truncated glycosyl acceptors were unsuccessful. The route was used to produce 2.1 g of metabolite in eight steps from 2-chloro-5-hydroxypyridine in 21% overall yield.


Subject(s)
Benzimidazoles/chemistry , Glucuronides/chemistry , Glucuronides/chemical synthesis , Piperazines/chemistry , Pyridines/chemistry , Benzimidazoles/metabolism , Dopamine Agonists/chemistry , Dopamine Agonists/metabolism , Esters/chemistry , Esters/metabolism , Glucuronides/metabolism , Molecular Structure , Piperazines/metabolism , Pyridines/metabolism
14.
Bioorg Med Chem ; 13(15): 4667-78, 2005 Aug 01.
Article in English | MEDLINE | ID: mdl-15896964

ABSTRACT

A series of 3-aryl piperidine analogs with 2-piperidinoalkylamino or 2-piperidinoalkyloxy fused bicyclic rings were prepared and found to be potent and efficacious human dopamine D4 agonists. The synthesis and structure-activity relationship (SAR) studies that led to the identification of these compounds are discussed.


Subject(s)
Dopamine Agonists/chemical synthesis , Dopamine Agonists/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Receptors, Dopamine D2/agonists , Cell Line , Dopamine Agonists/chemistry , Humans , Ligands , Molecular Structure , Piperidines/chemical synthesis , Receptors, Dopamine D4 , Structure-Activity Relationship
15.
J Med Chem ; 47(15): 3853-64, 2004 Jul 15.
Article in English | MEDLINE | ID: mdl-15239663

ABSTRACT

A new class of agents with potential utility for the treatment of erectile dysfunction has been discovered, guided by the hypothesis that selective D4 agonists are erectogenic but devoid of the side effects typically associated with dopaminergic agents. The lead agent 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (1, ABT-724) was discovered by optimization of a series of benzimidazole arylpiperazines. This highly selective D4 agonist was found to be very potent and efficacious in vivo, eliciting penile erections in rats at a dose of 0.03 micromol/kg, with a positive response rate of 77% erectile incidence. Even at high doses, it was devoid of side effects in animal models of central nervous system behaviors, emesis, or nausea. The structure-activity relationship of the parent benzimidazole series leading to 1 is described, with the detailed in vitro and in vivo profiles described. Distinctive structural features were discovered that are associated with D4 selective agonism in this series of analogues.


Subject(s)
Benzimidazoles/chemical synthesis , Erectile Dysfunction/drug therapy , Piperazines/chemical synthesis , Pyridines/chemical synthesis , Receptors, Dopamine D2/agonists , Animals , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Benzimidazoles/toxicity , Cell Line , Ferrets , Humans , Male , Penile Erection/drug effects , Piperazines/chemistry , Piperazines/pharmacology , Piperazines/toxicity , Pyridines/chemistry , Pyridines/pharmacology , Pyridines/toxicity , Radioligand Assay , Rats , Rats, Wistar , Receptors, Dopamine D4 , Structure-Activity Relationship , Vomiting/chemically induced
16.
J Med Chem ; 47(9): 2348-55, 2004 Apr 22.
Article in English | MEDLINE | ID: mdl-15084133

ABSTRACT

A series of subtype selective dopamine D(4) receptor ligands from the hetroarylmethylphenylpiperazine class have been discovered that exhibit a remarkable structure-activity relationship (SAR), revealing a substituent effect in which regiosubstitution on the terminal arylpiperazine ring can modulate functional or intrinsic activity. Other structure-dependent efficacy studies in the dopamine D(4) field have suggested a critical interaction of the heteroarylmethyl moiety with specific protein microdomains in controlling intrinsic activity. Our studies indicate that for some binding orientations, the phenylpiperazine moiety also plays a key role in determining efficacy. These data also implicate a kinetic or efficiency term, contained within measured functional affinities for agonists, which support a sequential binding and conformational stabilization model for receptor activation. The structural similarity between partial agonist and antagonist, within this subset of ligands, and lack of bioisosterism for this substituent effect are key phenomena for these hypotheses.


Subject(s)
Benzimidazoles/chemical synthesis , Piperazines/chemical synthesis , Pyridines/chemical synthesis , Receptors, Dopamine D2/agonists , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Binding, Competitive , Cell Line , Dopamine D2 Receptor Antagonists , Humans , Ligands , Piperazines/chemistry , Piperazines/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Radioligand Assay , Receptors, Dopamine D4 , Structure-Activity Relationship , Thermodynamics
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