Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing
Reexamination Certificate
1998-12-18
2001-07-31
Jones, Dameron L. (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
C514S743000, C514S760000, C424S009200
Reexamination Certificate
active
06267945
ABSTRACT:
TECHNICAL FIELD
The invention relates to compounds useful in treating conditions associated with calcium channel function. More specifically, the invention concerns compounds related to farnesol that are useful in treatment of conditions such as stroke and pain.
BACKGROUND ART
Native calcium channels have been classified by their electrophysiological and pharmacological properties as T, L, N, P and Q types (for reviews see McCleskey, E. W. et al.
Curr Topics Membr
(1991) 39:295-326, and Dunlap, K. et al.
Trends Neurosci
(1995) 18:89-98). T-type (or low voltage-activated) channels describe a broad class of molecules that transiently activate at negative potentials and are highly sensitive to changes in resting potential. The L, N, P and Q-type channels activate at more positive potentials and display diverse kinetics and voltage-dependent properties. There is some overlap in biophysical properties of the high voltage-activated channels, consequently pharmacological profiles are useful to further distinguish them. L-type channels are sensitive to dihydropyridine agonists and antagonists, N-type channels are blocked by the
Conus geographus
peptide toxin, &ohgr;-conotoxin GVIA, and P-type channels are blocked by the peptide &ohgr;-agatoxin IVA from the venom of the funnel web spider,
Agelenopsis aperta.
A fourth type of high voltage-activated calcium channel (Q-type) has been described, although whether the Q- and P-type channels are distinct molecular entities is controversial (Sather, W. A. et al.
Neuron
(1995) 11:291-303; Stea, A. et al.
Proc Natl Acad Sci USA
(1994) 91:10576-10580). Several types of calcium conductances do not fall neatly into any of the above categories and there is variability of properties even within a category suggesting that additional calcium channels subtypes remain to be classified.
Biochemical analyses show that neuronal high-threshold calcium channels are heterooligomeric complexes consisting of three distinct subunits (&agr;
1
, &agr;
2
&dgr; and &bgr;) (reviewed by De Waard, M. et al.
Ion Channels
(1997) vol. 4, Narahashi, T. ed. Plenum Press, New York). The &agr;
1
subunit is the major pore-forming subunit and contains the voltage sensor and binding sites for calcium channel antagonists. The mainly extracellular &agr;
2
is disulfide-linked to the transmembrane &dgr; subunit and both are derived from the same gene and are proteolytically cleaved in vivo. The &bgr; subunit is a nonglycosylated, hydrophilic protein with a high affinity of binding to a cytoplasmic region of the &agr;
1
subunit. A fourth subunit, &ggr;, is unique to L-type calcium channels expressed in skeletal muscle T-tubules. The isolation and characterization of y-subunit-encoding cDNAs is described in U.S. Pat. No. 5,386,025 which is incorporated herein by reference.
Recently, each of these &agr;
1
subtypes has been cloned and expressed, thus permitting more extensive pharmacological studies. These channels have been designated &agr;
1A
-&agr;
1H
and &agr;
1S
and correlated with the subtypes set forth above. &agr;
1A
channels are of the P/Q type; &agr;
1B
represents N; &agr;
1C
, &agr;
1D
and &agr;
1S
represent L; &agr;
1E
represents a novel type of calcium conductance, and &agr;
1G
and &agr;
1H
represent two members of the T-type family, reviewed in Stea, A. et al. in Handbook of Receptors and Channels (1994), North, R. A. ed. CRC Press; Perez-Reyes, et al.
Nature
(1998) 391:896-900. Bech-Hansen et al.,
Nature Neurosci
(1998) 1:264-267.
U.S. Ser. No. 09/107,037 filed Jun. 30, 1998 describes compounds containing benzhydril and 6-membered heterocyclic moieties that show calcium-channel blocking activity, wherein certain members of the disclosed genus are specific to N-type channels. The present invention is directed to compounds structurally related to farnesol whose activity is also N-type specific at low concentrations. Farnesol has previously been shown to be a calcium-channel blocker when used in the micromolar range and to show a preference for inhibition of L-type receptors (Roullet, J.-B., et al.,
J Biol Chem
(1997) 272:32240-32246. This demonstrated activity is exhibited as “open channel” blockage; that is, channels that have been activated by depolarization show inhibited calcium ion flow. This is in contrast to the inactivated channel block which is exhibited, but at nanomolar concentrations, by farnesol and its related compounds and is specific to the N-type channel. Accordingly, these compounds which, like farnesol, promote the inactivation of the N-type channels, preferably at physiological background potential conditions, are useful in treating conditions associated with N-type channel activity, such as stroke and pain.
DISCLOSURE OF THE INVENTION
The invention relates to compounds useful in treating conditions such as stroke, chronic and acute pain, epilepsy, hypertension, cardiac arrhythmias, and other indications associated with calcium physiology. The compounds of the invention are related structurally to farnesol and can contain substituents that enhance the specificity of the inactivation inhibition of N-type channels. Thus, in one aspect, the invention is directed to therapeutic methods that employ compounds containing a straight backbone carbon chain of 8-16C optionally substituted with 1-5 alkyl groups (1-6C). The compounds may optionally be functionalized at one terminus with halo, —OR, —SR, —NR
2
, —OOCR, —NROCR, where R is H or alkyl (1-6C) or phosphate or pyrophosphate, or a terminal carbon is optionally in the form of —COOR, —CONR
2
or —COR, where R is H or alkyl (1-6C). The backbone chain may optionally contain 1-4 &pgr;-bonds or the epoxides thereof.
The invention is directed to methods to antagonize calcium channel activity using these compounds and thus to treat associated conditions. It will be noted that the conditions may be associated with abnormal calcium channel activity, or the subject may have normal calcium channel function which nevertheless results in an undesirable physical or metabolic state. In another aspect, the invention is directed to pharmaceutical compositions containing these compounds.
The invention is also directed to combinatorial libraries containing the compounds of the invention and to methods to screen these libraries for members containing particularly potent calcium channel inactivating activity or for members that antagonize other channels.
REFERENCES:
patent: 5386025 (1995-01-01), Jay et al.
patent: 0 476682A (1992-03-01), None
patent: 0 609440A (1994-08-01), None
patent: 1403851A (1975-08-01), None
patent: 62-093225A (1987-04-01), None
patent: 7-126202A (1995-05-01), None
patent: 8-176083A (1996-07-01), None
patent: WO 98 02182A (1998-01-01), None
patent: WO 98 54123A (1998-12-01), None
Roullet et al, J. Clin. Invest., vol. 97, No. 10, pp. 2384-2390, “Farnesyl Analogues Inhibit Vasoconstriction in Animal and Human Arteries”, May 15, 1996.*
Roullet et al, Hypertension, vol. 28, No. 3, p. 519, Abstract II 63, “Farnesyl Analogs Inhibit Ca2+Signaling in Smooth Muscle Cells and Arteries”, Sep. 1996.*
Roullet et al, Hypertension, vol. 26, No. 3, p. 568, Abstract II P100, “Fainesol, a Non-Sterol derivative of Mevalonic Acid (MVA) is a potent Vasodilator”, Sep. 1995.*
Roullet et al, FASEB, Journal, vol. 10, No. 3, A696, Abstract II 4021, “Farnesol inhibits arginine-vasopressin (AVP) response in rat resistance arteries and vascular smooth muscle cells (VSMC),” Apr. 14-17, 1996.*
Roullet et al, J. Biological Chemistry, vol. 272, No. 51, pp. 32240-32246, “Farnesol Inhibits L-type Ca2+channels in vascular smooth muscle cells,” Dec. 19, 1997.*
Roulett J.B. et al. (1996). “Farnesyl Analogues Inhibit Vasoconstriction in Animal and Human Arteries,”Journal of Clinical Investigation97 (10):2384-2390.
Roulett J.B. et al. (1999). “Modulation of Neuronal Voltage-gated Calcium Channels by Farnesol,”J. Biol Chem274 (36):25439-25446.
Bech-Hansen et al., “Loss-of-Function Mutations in a Calcium-Channel &agr;1-Subunit Gene in Xp11.23 Cause Incomplete X-linked Congenital Stationary Night Blindness
Jones Dameron L.
Morrison & Foerster / LLP
Neuromed Technologies, Inc.
LandOfFree
Farnesol-related calcium channel blockers does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Farnesol-related calcium channel blockers, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Farnesol-related calcium channel blockers will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2550594