Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-09
2002-11-12
Rao, Deepak R. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S275000, C544S325000, C544S326000, C544S327000, C544S329000
Reexamination Certificate
active
06479498
ABSTRACT:
BACKGROUND
1. Field of the Invention
This invention relates to novel multibinding compounds that bind to sodium (Na
+
) channels and modulate their activity. The compounds of this invention comprise 2-10 Na
+
channel ligands covalently connected by a linker or linkers, wherein the ligands in their monovalent (i.e., unlinked) state bind to and are capable of modulating the activity of one or more types of Na
+
channel. The manner of linking the ligands together is such that the nultibinding agents thus formed demonstrate an increased biologic and/or therapeutic effect as compared to the same number of unlinked ligands made available for binding to the Na
+
channel. The invention also relates to methods of using such compounds and to methods of preparing them.
The compounds of this invention are particularly useful for treating diseases and conditions of mammals that are mediated by Na
+
channels. Accordingly, this invention also relates to pharmaceutical compositions comprising a pharmaceutically acceptable excipient and an effective amount of a compound of this invention.
2. State of the Art
Voltage-gated ion channels play a critical role in shaping the electrical activity of neuronal and muscle cells, and in controlling the secretion of neurotransmitters and hormones through the gating of calcium ion entry. Large families of voltage-gated sodium (Na
+
), potassium (K
+
) and calcium (Ca
2+
) ion channels have been defined using electrophysiological, pharmacological and molecular techniques; they are named according to their selective permeability for a particular cation with reference to their voltage dependence, kinetic behavior or molecular identity.
Although the structures of Na
+
, K
+
and Ca
2+
channels are quite different, there are common functional elements represented in each. The channels are all transmembrane proteins with an ion-selective aqueous pore that, when open, extends across the membrane. Channel opening and closing (gating) is controlled by a voltage-sensitive region of the protein containing charged amino acids that move within the electric field. The movement of these charged groups leads to conformational changes in the structure of the channel resulting in conducting (open/activated) or nonconducting (closed/inactivated) states.
Voltage-gated Na
+
channels mediate regenerative inward currents that are responsible for the initial depolarization of action potentials in brain neurons. Na
+
channels are large glycoproteins that consist of various subunits, the principal one being the alpha (&agr;) subunit. Na
+
channels exist as dimers in cardiac and skeletal muscles and exist as heterotrimers in neuronal cells.
FIG. 1A
shows that the a subunit has a modular architecture; it consists of four internally homologous domains (labeled I-IV), each of which contains six transmembrane segments. Prominant phosphorylation sites of the a subunit are also shown. The four domains fold together so as to create a central pore whose structural constituents determine the selectivity and conductance properties of the channel as shown in FIG.
1
B. Auxiliary beta (&bgr;) subunits are important modulators of Na
+
channel function. Biochemical studies reveal the existence of two distinct &bgr; subunits (&bgr;1 and &bgr;2) associated with the brain Na
+
channel. It should be understood that, for purposes of simplification, other subunits that may be involved in or required for transporter activity have been omitted from the diagrams.
Na
+
channels can exist in multiple ion conducting (open) and nonconducting (closed/inactivated) conformations.
FIG. 2A
illustrates how Na
+
channels open and then rapidly inactivate following voltage stimulation. Transitions between these states occurs in a voltage and time-dependent manner. The time course and voltage dependency of Na
+
-channel activity can be described by separate activation and inactivation gating processes. Activation takes place upon depolarization of the membrane (&Dgr;V
m
) and the channel adopts an open pore conformation allowing Na
+
influx. Inactivation processes then change the channel conformation to a nonconducting, non-activatable state. Repolarization returns the channels from inactivated to resting conformations.
FIG. 2B
illustrates how Na
+
channel opening may be prolonged by toxin binding. Toxins such as veratridine and batrachotoxin are activators that can bind to channels in the open conformation and stabilize the channel in a modified conducting state. This in effect removes or slows down the inactivation process allowing ion flux to continue from minutes to hours. Conversely, toxins such as tetrodotoxin (TTX) are blockers that can bind to the channel in the inactivated conformations. One method of distinguishing different Na
+
channels is whether they are TTX-sensitive or TTX-resistant. (See, for example, Denyer, et al., “HTS Approaches to Voltage-Gated Ion Channel Drug Discovery”,
DDT
, 3, No. 7, 323-332 (1998); Whalley, et al., “Basic Concepts in Cellular Cardiac Electrophysiology: Part II: Block of Ion Channels by Antiarrhythmic Drugs”,
PACE
, 18, Part I, 1686-1704 (1995); Goodman & Gilman's “The Pharmacological Basis of Therapeutics” McGraw-Hill, Ninth Ed. Ch. 35, 851-856; and Doggrell, et al., “Ion channel Modulators as Potential Positive Inotropic Compounds for Treatment of Heart Failure”,
Clinical and Experimental Pharmacology and Physiology
, 21, 833-843, 1994.)
Sodium channel blockers/modulators are employed to alleviate various disease conditions including, but not limited to, epilepsy, pain, anaesthesia, neuroprotection, arrhythmia, and migraine. (See, for example, PCT Publication WO 96/20935, European Patent Application EP 0869119, PCT Publication WO 97/27169, U.S. Pat. No. 5,688,830, Hunter & Loughhead “Voltage-Gated Sodium Channel Blockers for the Treatment of Chronic Pain”,
Current Opinion in CPNS Investigational Drugs
, 1999, vol. 1, no. 1, 72-81 and Loughhead et al., “Synthesis of Mexiletine Stereoisomers and Related Compounds via S
N
Ar Nucleophilic Substitution of a Cr(CO)
8
-Complexed Aromatic Fluoride”
J. Org. Chem
. 1999, 64, 3373-3375.) Antiepileptic agents, include, for example, phenytoin, carbamazepine, and lamotrigine. Phenytoin is the prototypic antiepileptic sodium channel blocker and is efficacious in treating partial and generalized tonic-clonic seizures in humans. One important property of phenytoin is that it is capable of preventing seizures without producing sedation. Thus, phenytoin was the first antiepileptic to approach the therapeutic ideal of inhibiting abnormal brain activity characteristic of seizures without appreciably interfering with normal brain activity.
Carbamazepine, an iminostilbene derivative of tricyclic antidepressants, exhibits a spectrum of anticonvulsant activity very similar to that of phenytoin. In humans, it is effective against partial and generalized tonic-clonic seizures, but not against absence seizures. Lamotrigine has been used for treating partial and generalized tonic-clonic seizure.
Topiramate is a sulfamate-substituted monosaccharide, with a phenytoin-like profile in the maximal electroshock and pentylenetetrazol tests. These studies have also shown that it can control seizures in some genetic epilepsy models, in amygdala-kindled rats and in animals with ischemia-induced epilepsy. Clinical studies have shown that topiramate is effective as an add-on drug for treating simple or complex partial seizures with or without secondary generalization, even when administrered as monotherapy.
The clinical shortcomings of drugs in current usage are considerable. For example, lamotrigine causes rash and sedation and topiramate, phenytoin, and carbamazepine causes central nervous system side effects.
Thus, there continues to exist a need for novel compounds having improved therapeutic activities (e.g., increased potency, greater tissue selectivity, increased efficacy, reduced side effects and a more favorable dur
Armstrong Scott
Beattie David T.
Choi Seok-Ki
Church Timothy J.
Green David C.
Boone David E.
Hagenah Jeffrey A.
Rao Deepak R.
Saxon Roberta P.
Theravance Inc.
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