-
Michael E Kort,
Robert N Atkinson,
James B Thomas,
Irene Drizin,
Matthew S Johnson,
Matthew A Secrest,
Robert J Gregg,
Marc J C Scanio,
Lei Shi,
Ahmed H Hakeem, [......],
Shailen Joshi,
Prisca Honore,
Rosemarie Roeloffs,
Stephen Werness,
Brett Antonio,
Kennan C Marsh,
Connie R Faltynek,
Douglas S Krafte,
Michael F Jarvis,
Brian E Marron
[show abstract]
[hide abstract]
ABSTRACT: A series of aryl-substituted nicotinamide derivatives with selective inhibitory activity against the Na(v)1.8 sodium channel is reported. Replacement of the furan nucleus and homologation of the anilide linker in subtype-selective blocker A-803467 (1) provided potent, selective derivatives with improved aqueous solubility and oral bioavailability. Representative compounds from this series displayed efficacy in rat models of inflammatory and neuropathic pain.
Bioorganic & medicinal chemistry letters 11/2010; 20(22):6812-5. · 2.65 Impact Factor
-
Xu-Feng Zhang,
Char-Chang Shieh,
Mark L Chapman, Mark A Matulenko,
Ahmed H Hakeem,
Robert N Atkinson,
Michael E Kort,
Brian E Marron,
Shailen Joshi,
Prisca Honore,
Connie R Faltynek,
Douglas S Krafte,
Michael F Jarvis
[show abstract]
[hide abstract]
ABSTRACT: Activation of sodium channels is essential to action potential generation and propagation. Recent genetic and pharmacological evidence indicates that activation of Na(v)1.8 channels contributes to chronic pain. Herein, we describe the identification of a novel series of structurally related pyridine derivatives as potent Na(v)1.8 channel blockers. A-887826 exemplifies this series and potently (IC(50)=11nM) blocked recombinant human Na(v)1.8 channels. A-887826 was approximately 3 fold less potent to block Na(v)1.2, approximately 10 fold less potent to block tetrodotoxin-sensitive sodium (TTX-S Na(+)) currents and was >30 fold less potent to block Na(V)1.5 channels. A-887826 potently blocked tetrodotoxin-resistant sodium (TTX-R Na(+)) currents (IC(50)=8nM) from small diameter rat dorsal root ganglion (DRG) neurons in a voltage-dependent fashion. A-887826 effectively suppressed evoked action potential firing when DRG neurons were held at depolarized potentials and reversibly suppressed spontaneous firing in small diameter DRG neurons from complete Freund's adjuvant inflamed rats. Following oral administration, A-887826 significantly attenuated tactile allodynia in a rat neuropathic pain model. Further characterization of TTX-R current block in rat DRG neurons demonstrated that A-887826 (100nM) shifted the mid-point of voltage-dependent inactivation of TTX-R currents by approximately 4mV without affecting voltage-dependent activation and did not exhibit frequency-dependent inhibition. The present data demonstrate that A-887826 is a structurally novel and potent Na(v)1.8 blocker that inhibits rat DRG TTX-R currents in a voltage-, but not frequency-dependent fashion. The ability of this structurally novel Na(v)1.8 blocker to effectively reduce tactile allodynia in neuropathic rats further supports the role of Na(v)1.8 sodium channels in pathological pain states.
Neuropharmacology 09/2010; 59(3):201-7. · 4.81 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The voltage-gated sodium channels are a family of proteins that control the flow of sodium ions across cell membranes. Considerable data support the hypothesis that hyperexcitability and spontaneous action potential firing in peripheral sensory neurons mediated by voltage-gated sodium channels contribute to the pathophysiology of chronic pain. Sodium channel blockers are, therefore, appealing entities for therapeutic intervention in painful human neuropathies. This review will focus on the latest advances in the development of small molecule sodium channel blockers and their application to the treatment of chronic pain.
Current topics in medicinal chemistry 02/2009; 9(4):362-76. · 4.47 Impact Factor
-
Mark A Matulenko,
Ernest S Paight,
Robin R Frey,
Arthur Gomtsyan,
Stanley DiDomenico,
Meiqun Jiang,
Chih-Hung Lee,
Andrew O Stewart,
Haixia Yu,
Kathy L Kohlhaas,
Karen M Alexander,
Steve McGaraughty,
Joseph Mikusa,
Kennan C Marsh,
Steven W Muchmore,
Clarissa L Jakob,
Elizabeth A Kowaluk,
Michael F Jarvis,
Shripad S Bhagwat
[show abstract]
[hide abstract]
ABSTRACT: A series of non-nucleoside adenosine kinase (AK) inhibitors is reported. These inhibitors originated from the modification of 5-(3-bromophenyl)-7-(6-morpholin-4-ylpyridin-3-yl)pyrido[2,3-d]pyrimidin-4-ylamine (ABT-702). The identification of a linker that would approximate the spatial arrangement found between the pyrimidine ring and the aryl group at C(7) in ABT-702 was a key element in this modification. A search of potential linkers led to the discovery of an acetylene moiety as a suitable scaffold. It was hypothesized that the aryl acetylenes, ABT-702, and adenosine bound to the active site of AK (closed form) in a similar manner with respect to the orientation of the heterocyclic base. Although potent acetylene analogs were discovered based on this assumption, an X-ray crystal structure of 5-(4-dimethylaminophenyl)-6-(6-morpholin-4-ylpyridin-3-ylethynyl)pyrimidin-4-ylamine (16a) revealed a binding orientation contrary to adenosine. In addition, this compound bound tightly to a unique open conformation of AK. The structure-activity relationships and unique ligand orientation and protein conformation are discussed.
Bioorganic & Medicinal Chemistry 03/2007; 15(4):1586-605. · 2.92 Impact Factor
-
Meena V Patel,
Teodozyj Kolasa,
Kathleen Mortell, Mark A Matulenko,
Ahmed A Hakeem,
Jeffrey J Rohde,
Sherry L Nelson,
Marlon D Cowart,
Masaki Nakane,
Loan N Miller, [......],
Jill M Wetter,
Kennan C Marsh,
Ruth Martin,
John F Darbyshire,
Gary Gintant,
Gin C Hsieh,
Robert B Moreland,
James P Sullivan,
Jorge D Brioni,
Andrew O Stewart
[show abstract]
[hide abstract]
ABSTRACT: The goal of this study was to identify a structurally distinct D(4)-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.
Journal of Medicinal Chemistry 01/2007; 49(25):7450-65. · 5.25 Impact Factor
-
Steven W Muchmore,
Richard A Smith,
Andrew O Stewart,
Marlon D Cowart,
Arthur Gomtsyan, Mark A Matulenko,
Haixia Yu,
Jean M Severin,
Shripad S Bhagwat,
Chih-Hung Lee,
Elizabeth A Kowaluk,
Michael F Jarvis,
Clarissa L Jakob
[show abstract]
[hide abstract]
ABSTRACT: Adenosine kinase (AK) is an enzyme responsible for converting endogenous adenosine (ADO) to adenosine monophosphate (AMP) in an adenosine triphosphate- (ATP-) dependent manner. The structure of AK consists of two domains, the first a large alpha/beta Rossmann-like nucleotide binding domain that forms the ATP binding site, and a smaller mixed alpha/beta domain, which, in combination with the larger domain, forms the ADO binding site and the site of phosphoryl transfer. AK inhibitors have been under investigation as antinociceptive, antiinflammatory, and anticonvulsant as well as antiinfective agents. In this work, we report the structures of AK in complex with two classes of inhibitors: the first, ADO-like, and the second, a novel alkynylpyrimidine series. The two classes of structures, which contain structurally similar substituents, reveal distinct binding modes in which the AK structure accommodates the inhibitor classes by a 30 degrees rotation of the small domain relative to the large domain. This change in binding mode stabilizes an open and a closed intermediate structural state and provide structural insight into the transition required for catalysis. This results in a significant rearrangement of both the protein active site and the orientation of the alkynylpyrimidine ligand when compared to the observed orientation of nucleosidic inhibitors or substrates.
Journal of Medicinal Chemistry 12/2006; 49(23):6726-31. · 5.25 Impact Factor
-
Teodozyj Kolasa, Mark A Matulenko,
Ahmed A Hakeem,
Meena V Patel,
Kathleen Mortell,
Pramila Bhatia,
Rodger Henry,
Masaki Nakane,
Gin C Hsieh,
Marc A Terranova, [......],
Diana L Donnelly-Roberts,
Marian T Namovic,
Peter R Hollingsworth,
Brenda Martino,
Odile El Kouhen,
Kennan C Marsh,
Jill M Wetter,
Robert B Moreland,
Jorge D Brioni,
Andrew O Stewart
[show abstract]
[hide abstract]
ABSTRACT: A new series of dopamine D4 receptor agonists, 1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes, was designed through the modification of known dopamine D4 receptor agonist PD 168077. Replacement of the amide group with a methylene-oxime moiety produced compounds with improved stability and efficacy. Structure-activity relationsips (SAR) of the aromatic ring linked to the N-4-piperazine ring confirmed the superiority of 2-pyridine as a core for D4 agonist activity. A two-methylene linker between the oxime group and the N-1-piperazine ring displayed the best profile. New dopamine D4 receptor agonists, exemplified by (E)-1-(4-chlorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-methyloxime (59a) and (E)-1-(3-chloro-4-fluorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-methyloxime (64a), exhibited favorable pharmacokinetic profiles and showed oral bioavailability in rat and dog. Subsequent evaluation of 59a in the rat penile erection model revealed in vivo activity, comparable in efficacy to apomorphine. Our results suggest that the oximes provide a novel structural linker for 4-arylpiperazine-based D4 agonists, possessing leadlike quality and with potential to develop a new class of potent and selective dopamine D4 receptor agonists.
Journal of Medicinal Chemistry 09/2006; 49(17):5093-109. · 5.25 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Acid Sensing Ion Channels (ASICs) are a group of sodium-selective ion channels that are activated by low extracellular pH. The role of ASIC in disease states remains unclear partly due to the lack of selective pharmacological agents. In this report, we describe the effects of A-317567, a novel non-amiloride blocker, on three distinct types of native ASIC currents evoked in acutely dissociated adult rat dorsal root ganglion (DRG) neurons. A-317567 produced concentration-dependent inhibition of all pH 4.5-evoked ASIC currents with an IC50 ranging between 2 and 30muM, depending upon the type of ASIC current activated. Unlike amiloride, A-317567 equipotently blocked the sustained phase of ASIC3-like current, a biphasic current akin to cloned ASIC3, which is predominant in DRG. When evaluated in the rat Complete Freud's Adjuvant (CFA)-induced inflammatory thermal hyperalgesia model, A-317567 was fully efficacious at a dose 10-fold lower than amiloride. A-317567 was also potent and fully efficacious when tested in the skin incision model of post-operative pain. A-317567 was entirely devoid of any diuresis or natriuresis activity and showed minimal brain penetration. In summary, A-317567 is the first reported small molecule non-amiloride blocker of ASIC that is peripherally active and is more potent than amiloride in vitro and in vivo pain models. The discovery of A-317567 will greatly help to enhance our understanding of the physiological and pathophysiological role of ASICs.
Pain 10/2005; 117(1-2):88-96. · 5.78 Impact Factor
-
Xueqing Wang,
Pramila A Bhatia,
Jerome F Daanen,
Steve P Latsaw,
Jeffrey Rohde,
Teodozyi Kolasa,
Ahmed A Hakeem, Mark A Matulenko,
Masaki Nakane,
Marie E Uchic,
Loan N Miller,
Renjie Chang,
Robert B Moreland,
Jorge D Brioni,
Andrew O Stewart
[show abstract]
[hide abstract]
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.
Bioorganic & Medicinal Chemistry 09/2005; 13(15):4667-78. · 2.92 Impact Factor
-
Mark A Matulenko,
Chih-Hung Lee,
Meiqun Jiang,
Robin R Frey,
Marlon D Cowart,
Erol K Bayburt,
Stanley Didomenico,
Gregory A Gfesser,
Arthur Gomtsyan,
Guo Zhu Zheng, [......],
Karen M Alexander,
Steve McGaraughty,
Carol T Wismer,
Joseph Mikusa,
Kennan C Marsh,
Ronald D Snyder,
Marilyn S Diehl,
Elizabeth A Kowaluk,
Michael F Jarvis,
Shripad S Bhagwat
[show abstract]
[hide abstract]
ABSTRACT: 4-Amino-5,7-disubstituted pyridopyrimidines are potent, non-nucleoside inhibitors of adenosine kinase (AK). We recently identified a potent, orally efficacious analog, 4 containing a 7-pyridylmorpholine substituted ring system as the key structural element of this template. In this report, we disclose the pharmacologic effects of five- and six-membered heterocyclic ring replacements for the pyridine ring in 4. These replacements were found to have interesting effects on in vivo efficacy and genotoxicity as well as in vitro potency. We discovered that the nitrogen in the heterocyclic ring at C(7) is important for the modulation of mutagenic side effects (Ames assay).
Bioorganic & Medicinal Chemistry 07/2005; 13(11):3705-20. · 2.92 Impact Factor
-
Mark A Matulenko,
Bruce Surber,
Leimin Fan,
Teodozyi Kolasa,
Masaki Nakane,
Marc A Terranova,
Marie E Uchic,
Loan N Miller,
Renjie Chang,
Diana L Donnelly-Roberts,
Marian T Namovic,
Robert B Moreland,
Jorge D Brioni,
Andrew O Stewart
[show abstract]
[hide abstract]
ABSTRACT: The first selective dopamine D4 agonist radioligand is described. The synthesis of these piperazine radioligands relied on the transformation of brominated precursors 4a and 4b with tritium gas in the presence of a sensitive cyano functional group. The specific activity of these two radioligands was measured and [3H]6b found to be suitable for use in D4 saturation and competition binding studies. The synthesis, biological, and radioactivity of this new agonist radioligand as well as preliminary SAR will be discussed.
Bioorganic & Medicinal Chemistry Letters 11/2004; 14(20):5095-8. · 2.55 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Tritiation of the dopamine D(4) receptor selective agonist A-369508 ([2-[4-(2-cyanophenyl)-1-piperazinyl]-N-(3-methylphenyl) acetamide) has provided a radioligand for the characterization of dopamine D(4) receptors. [(3)H] A-369508 binds with high affinity to the major human dopamine D(4) receptor variants D(4.2), D(4.4) and D(4.7) (K(d)=1.7, 4, and 1.2 nM, respectively). It also binds to the rat dopamine D(4) receptor, (K(d)=4.4 nM), implying similar binding affinity across human and rat receptors. A-369508 shows >400-fold selectivity over D(2L), >350-fold selectivity over 5-HT(1A) and >700-1,000-fold selectivity over all other receptors tested. Agonist activity determined by inhibition of forskolin-induced cAMP in Chinese hamster ovary cells transfected with the human dopamine D(4.4) receptor (EC(50)=7.5 nM, intrinsic activity=0.71) indicates that A-369508 is a potent agonist at the human dopamine D(4) receptor. Similar data was observed in other functional assays. [(3)H] A-369508 binds to a single, high affinity site on membranes containing the human dopamine D(4.4) receptor. When compared to the D(2)-like antagonist [(3)H] spiperone, competition binding for agonists like dopamine and apomorphine were 2-10-fold more potent with [(3)H] A-369508, while the antagonists clozapine, haloperidol and L-745870 bind with similar affinity to both ligands. Binding to rat brain regions demonstrated that the most abundant area was cerebral cortex (51.2 fmol/mg protein) followed by hypothalamus, hippocampus, striatum and cerebellum. [(3)H] A-369508 is a useful tool to define the localization and physiological role of dopamine D(4) receptors in central nervous system and can facilitate measuring accurate affinities (K(i)) for structure/activity relationship studies designed to identify dopamine D(4) receptor selective agonists.
European Journal of Pharmacology 09/2004; 497(2):147-54. · 2.52 Impact Factor
-
Mark A Matulenko,
Ahmed A Hakeem,
Teodozyi Kolasa,
Masaki Nakane,
Marc A Terranova,
Marie E Uchic,
Loan N Miller,
Renjie Chang,
Diana L Donnelly-Roberts,
Marian T Namovic,
Robert B Moreland,
Jorge D Brioni,
Andrew O Stewart
[show abstract]
[hide abstract]
ABSTRACT: Diaryl piperazine acetamides were identified as potent and selective dopamine D(4) receptor agonists. Our strategy is based on an amide bond reversal of an acid sensitive, dopamine D(4) receptor partial agonist, PD 168077. This reversal provided compounds with excellent potency and improved stability. Systematic evaluation of the substitution on the aryl piperazine portion revealed a significant effect on functional activity. The synthesis and biological activity of these new dopamine D(4) agonists is discussed.
Bioorganic & Medicinal Chemistry 08/2004; 12(13):3471-83. · 2.92 Impact Factor
-
Andrew O Stewart,
Marlon D Cowart,
Robert B Moreland,
Steve P Latshaw, Mark A Matulenko,
Pramila A Bhatia,
Xueqing Wang,
Jerome F Daanen,
Sherry L Nelson,
Marc A Terranova,
Marian T Namovic,
Diana L Donnelly-Roberts,
Loan N Miller,
Masaki Nakane,
James P Sullivan,
Jorge D Brioni
[show abstract]
[hide abstract]
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.
Journal of Medicinal Chemistry 05/2004; 47(9):2348-55. · 5.25 Impact Factor
-
Arthur Gomtsyan,
Stanley Didomenico,
Chih-Hung Lee, Mark A Matulenko,
Ki Kim,
Elizabeth A Kowaluk,
Carol T Wismer,
Joe Mikusa,
Haixia Yu,
Kathy Kohlhaas,
Michael F Jarvis,
Shripad S Bhagwat
[show abstract]
[hide abstract]
ABSTRACT: Adenosine (ADO) is an extracellular signaling molecule within the central and peripheral nervous system. Its concentration is increased at sites of tissue injury and inflammation. One of the mechanisms by which antinociceptive and antiinflammatory effects of ADO can be enhanced consists of inhibition of adenosine kinase (AK), the primary metabolic enzyme for ADO. Novel nonnucleoside AK inhibitors based on 4-amino-6-alkynylpyrimidines were prepared, and the importance of the length of the linker at the 5-position for high affinity AK inhibition was demonstrated. Compounds with 2- and 3-atom linkers were the most potent AK inhibitors. Optimization of their physicochemical properties led to 31a and 37a that effectively reduced pain and inflammation in animal models.
Journal of Medicinal Chemistry 09/2002; 45(17):3639-48. · 5.25 Impact Factor
-
Xu-Feng Zhang,
Char-Chang Shieh,
Mark L. Chapman, Mark A. Matulenko,
Ahmed H. Hakeem,
Robert N. Atkinson,
Michael E. Kort,
Brian E. Marron,
Shailen Joshi,
Prisca Honore,
Connie R. Faltynek,
Douglas S. Krafte,
Michael F. Jarvis
[show abstract]
[hide abstract]
ABSTRACT: Activation of sodium channels is essential to action potential generation and propagation. Recent genetic and pharmacological evidence indicates that activation of Nav1.8 channels contributes to chronic pain. Herein, we describe the identification of a novel series of structurally related pyridine derivatives as potent Nav1.8 channel blockers. A-887826 exemplifies this series and potently (IC50 = 11nM) blocked recombinant human Nav1.8 channels. A-887826 was ∼3 fold less potent to block Nav1.2, ∼10 fold less potent to block tetrodotoxin-sensitive sodium (TTX-S Na+) currents and was >30 fold less potent to block NaV1.5 channels. A-887826 potently blocked tetrodotoxin-resistant sodium (TTX-R Na+) currents (IC50 = 8nM) from small diameter rat dorsal root ganglion (DRG) neurons in a voltage-dependent fashion. A-887826 effectively suppressed evoked action potential firing when DRG neurons were held at depolarized potentials and reversibly suppressed spontaneous firing in small diameter DRG neurons from complete Freund’s adjuvant inflamed rats. Following oral administration, A-887826 significantly attenuated tactile allodynia in a rat neuropathic pain model. Further characterization of TTX-R current block in rat DRG neurons demonstrated that A-887826 (100 nM) shifted the mid-point of voltage-dependent inactivation of TTX-R currents by ∼4 mV without affecting voltage-dependent activation and did not exhibit frequency-dependent inhibition. The present data demonstrate that A-887826 is a structurally novel and potent Nav1.8 blocker that inhibits rat DRG TTX-R currents in a voltage-, but not frequency-dependent fashion. The ability of this structurally novel Nav1.8 blocker to effectively reduce tactile allodynia in neuropathic rats further supports the role of Nav1.8 sodium channels in pathological pain states.
Neuropharmacology.
