Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-05-02
2002-10-22
Horlick, Kenneth R. (Department: 1637)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S082000
Reexamination Certificate
active
06468990
ABSTRACT:
BACKGROUND OF THE INVENTION
The neurotrophins are a family of structurally and functionally related proteins, including Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3), Neurotrophin-4/5 (NT-4/5) and Neurotrophin-6 (NT-6). These proteins promote the survival and differentiation of diverse neuronal populations in both the peripheral and central nervous systems (Hefti, 1986; Hefti and Weiner, 1986; Levi-Montalcini, 1987; Barde, 1989; Leibrock et al., 1989; Maisonpierre et al., 1990; Rosenthal et al., 1990; Hohn et al., 1990; Gotz et al., 1994; Maness et al., 1994) and are involved in the pathogenesis of diverse neurological disorders. Neurotrophins exert many of their biological effects through specific interactions with a class of transmembrane receptor tyrosine kinases (trkA, trkB and trkC) (Kaplan et al., 1991; Klein et al., 1991, 1992; Soppet et al., 1991; Squinto et al., 1991; Berkemeier et al., 1991; Escandon et al., 1993; Lamballe et al., 1991). Specificity of neurotrophin action results from their selective interactions with the trk receptors. That is, trkA only binds NGF (Kaplan et al., 1991; Klein et al., 1991); trkB binds BDNF and NT-4/5 (Soppet et al., 1991; Squinto et al., 1991; Berkemeier et al., 1991; Escandon et al., 1993; Lamballe et al., 1991; Klein et al., 1992; Vale and Shooter, 1985; Barbacid, 1993); and trkC exclusively binds NT-3 (Lamballe et al., 1991; Vale and Shooter, 1985). This is particularly evident when the trk receptors are coexpressed with the common neurotrophin receptor p75
NTR
. (For review see Meakin and Shooter, 1992; Barbacid, 1993; Chao, 1994; Bradshaw et al., 1994; Ibáñez, 1995).
The common neurotrophin receptor p75
NTR
is a transmembrane glycoprotein structurally related to the tumor necrosis factor and CD-40 receptors (Meakin and Shooter, 1992; Rydén and Ibáñez, 1996). As all neurotrophins bind to p75
NTR
with similar affinity (Rodriguez-Tébar et al., 1990; Hallböök et al., 1991; Rodriguez-Tébar et al., 1992; Ibáñez, 1995), neurotrophin specificity is conventionally thought to be caused by the binding selectivity for trk receptors which are differentially expressed in different neuronal populations (Ibáñez, 1995). However, accumulated experimental data on neurotrophin activity reveal important functional aspects of p75
NTR
(Heldin et al., 1989; Jing et al., 1992; Herrmann, 1993; Barker and Shooter, 1994; Dobrowsky et al., 1994, Matsumoto et al., 1995; Marchetti et al., 1996; Washiyama et al., 1996). The common neurotrophin receptor enhances functions and increases binding specificity of trk receptors (Barker and Shooter, 1994; Mahadeo et al., 1994; Chao and Hempstead, 1995; Rydén and Ibáñez, 1996). In addition, p75
NTR
possesses unique, trk-independent signaling properties which involve ceramide production through activation of the sphingomyelin cycle (Dobrowsky et al., 1994), apoptosis (cell death) (Van der Zee et al., 1996; Cassacia-Bonnefil et al., 1996; Frade et al., 1996), and activation of the transcription factor NF&kgr;B (Carter et al., 1996). Recently, p75
NTR
has been demonstrated to participate in human melanoma progression (Herrmann et al., 1993; Marchetti et al., 1996). Furthermore, NGF and NT-3 increase the production of heparin by 70W melanoma cells, which is associated with their metastatic potential (Marchetti et al., 1996). Although this effect has been shown to be mediated by the common neurotrophin receptor, neither BDNF nor NT-4/5 appeared to be active.
Due to the implication of NGF/p75
NTR
binding in various disease states, a need exists for pharmaceutical agents and methods of use thereof for interfering with the binding of NGF to the p75
NTR
common neurotrophin receptor.
SUMMARY OF THE INVENTION
The present invention relates to the discovery of molecular structural features which contribute to the ability of a compound to inhibit the binding of NGF to the common neurotrophin receptor p75
NTR
. Compounds which have these features are of use, for example, for inhibiting binding of NGF to p75
NTR
. Such compounds can also be used to treat a patient having a condition which is mediated, at least in part, by the binding of NGF to p75
NTR
.
In one embodiment, the present invention relates to compositions which inhibit the binding of nerve growth factor to the p75
NTR
common neurotrophin receptor and methods of use thereof.
In one embodiment, the compound which inhibits binding of nerve growth factor to p75
NTR
comprises at least two of the following: (1) a first electronegative atom or functional group positioned to interact with Lys
34
of nerve growth factor; (2) a second electronegative atom or functional group positioned to interact with Lys
95
of nerve growth factor; (3) a third electronegative atom or functional group positioned to interact with Lys
88
of nerve growth factor; (4) a fourth electronegative atom or functional group positioned to interact with Lys
32
of nerve growth factor; and (5) a hydrophobic moiety which interacts with the hydrophobic region formed by amino acid residues of nerve growth factor, including Ile
31
, Phe
86
and Phe
101
. Such inhibitors, preferably, bind nerve growth factor via at least two of the foregoing interactions.
In one embodiment, compounds which inhibit binding of nerve growth factor to p75
NTR
have Formula 1,
In Formula 1, D
1
, D
2
, E
1
, E
2
and G are each, independently, an sp
2
-hybridized carbon or nitrogen atom. One of X
1
and X
2
is a hydrogen atom or absent, while the other is an electronegative atom or an electronegative functional group. R and R
2
are each, independently, an electronegative atom or an electronegative functional group, such as O, S, CH
2
, or NR
3
, where R
3
is H, alkyl, preferably C
1
-C
6
-alkyl, or aryl, such as phenyl. R, R
2
and one of X
1
and X
2
can also each be, independently, an electronegative atom or functional group, such as alkylcarbonyl; alkylthiocarbonyl; alkoxycarbonyl; aminocarbonyl; —OH; —CN; —CO
2
H; —SO
3
H; —SO
2
H; —PO
3
H
2
; —NO
2
; —ONO
2
, —CNO, —SH, —CNS, —OSO
3
H, —OC(O)(OH); halomethyl, dihalomethyl or trihalomethyl group or a fluorine, chlorine, bromine or iodine atom. Y is N, O, S, C—L or N—L, where L is H, alkyl, preferably C
1
-C
6
-alkyl, or an electronegative atom or functional group, such as, but not limited to, alkylcarbonyl; alkylthiocarbonyl; alkoxycarbonyl; aminocarbonyl; —OH; —CN; —CO
2
H; —SO
3
H; —SO
2
H; —PO
3
H
2
; —NO
2
; —ONO
2
, —CNO, —SH, —CNS, —OSO
3
H, —OC(O)(OH); halomethyl, dihalomethyl or trihalomethyl groups or a halogen atom, such as a fluorine, chlorine, bromine or iodine atom. Z and Z
1
are each, independently, O, S, CH, C(O), N, NH, N-alkyl, N-cycloalkyl and N—P, where P is a carbohydrate moiety, such as a monosaccharide group, for example, a fucosyl, glucosyl, galactosyl, mannosyl, fructosyl, gulosyl, idosyl, talosyl, allosyl, altrosyl, ribosyl, arabinosyl, xylosyl or lyxosyl group. T
1
and T
2
are each, independently, an sp
2
- or sp
3
-hybridized carbon or nitrogen atom. a, b, and c are each 0 or 1, provided that at least one of b and c is 1. R
1
is a monocyclic or polycyclic aryl or heteroaryl, monosaccharide or oligosaccharide, alkyl, cycloalkyl, arylalkyl, alkylamino or alkoxy group which is substituted with at least one substituent selected from the group consisting of electronegative atoms and electronegative functional groups.
It will be appreciated that in this and the following structures, the lines connecting the variables can be single or double bonds. In addition, hydrogen atoms are added to the variables as necessary to complete the valence of the atom.
In another embodiment, the NGF/p75
NTR
binding inhibitor has Formula 3
where D
1
, D
2
, X
1
, X
2
, Y, E
1
, E
2
, T
1
, T
2
, R, G, R
1
, R
2
, and c have the meanings given above for these variables in Formula 1. Y
1
, Y
2
, and Y
3
are independently selected from the identities given for Y in Formula 1. E
3
and E
4
are each, independently, an sp
2
-hybridized carbon or nitrogen atom, and d and h are, independently, 0 or 1.
In another embodiment,
Marone Sandra
Riopelle Richard J.
Ross Gregory M.
Shamovsky Igor L.
Weaver Donald F.
Horlick Kenneth R.
Nassif Omar A.
Queen's University at Kingston
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