Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-10-06
2002-01-29
Raymond, Richard L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S654000, C514S452000, C514S466000, C564S319000, C564S378000, C564S380000, C564S383000, C549S362000, C549S440000
Reexamination Certificate
active
06342532
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compounds able to modulate one or more inorganic ion receptor activities.
BACKGROUND OF THE INVENTION
The references provided herein are not admitted to be prior art to the claimed invention.
Certain cells in the body respond not only to chemical signals, but also to ions such as extracellular calcium ions (Ca
2+
). Extracellular Ca
2+
is under tight homeostatic control and regulates various processes such as blood clotting, nerve and muscle excitability, and proper bone formation.
Calcium receptor proteins enable certain specialized cells to respond to changes in extracellular Ca
2+
concentration. For example, extracellular Ca
2+
inhibits the secretion of parathyroid hormone (PTH) from parathyroid cells, inhibits bone resorption by osteoclasts, and stimulates secretion of calcitonin from C-cells.
PTH is the principal endocrine factor regulating Ca
2+
homeostasis in the blood and extracellular fluids. PTH, by acting on bone and kidney cells, increases the level of Ca
2+
in the blood. This increase in extracellular Ca
2+
then acts as a negative feedback signal, depressing PTH secretion. The reciprocal relationship between extracellular Ca
2+
and PTH secretion forms an important mechanism maintaining bodily Ca
2+
homeostasis.
Extracellular Ca
2+
acts directly on parathyroid cells to regulate PTH secretion. The existence of a parathyroid cell surface protein which detects changes in extracellular Ca
2+
has been confirmed. (Brown et al.,
Nature
366:574, 1993.) In parathyroid cells, this protein, the calcium receptor, acts as a receptor for extracellular Ca
2+
, detects changes in the ion concentration of extracellular Ca
2+
, and initiates a functional cellular response, PTH secretion.
Extracellular Ca
2+
can exert effects on different cell functions, reviewed in Nemeth et al.,
Cell Calcium
11:319, 1990. The role of extracellular Ca
2+
in parafollicular (C-cells) and parathyroid cells is discussed in Nemeth,
Cell Calcium
11:323, 1990. These cells were shown to express similar calcium receptors. (See Brown et al.,
Nature
366:574, 1993; Mithal et al.,
J. Bone Miner. Res
. 9, Suppl. 1, s282, 1994; Rogers et al.,
J. Bone Miner. Res
. 9, Suppl, 1, s409, 1994; Garrett et al.,
Endocrinology
136:5202-5211, 1995.)
The ability of various molecules to mimic extracellular Ca
2+
in vitro is discussed in references such as Nemeth et al., in “Calcium-Binding Proteins in Health and Disease,” 1987, Academic Press, Inc., pp. 33-35; Brown et al.,
Endocrinology
128:3047, 1991; Chen et al.,
J. Bone Miner. Res
. 5:581, 1990; and Zaidi et al.,
Biochem. Biophys. Res. Commun
. 167:807, 1990.
Nemeth et al., PCT/US92/07175, International Publication Number WO 93/04373, Nemeth et al., PCT/US93/01642, International Publication Number WO 94/18959, and Nemeth et al., PCT/US94/12117, International Publication Number WO 95/11211, describe various compounds which can modulate the effect of an inorganic ion receptor.
SUMMARY OF THE INVENTION
The present invention features compounds able to modulate one or more activities of an inorganic ion receptor and methods for treating diseases or disorders using such compounds. Preferred compounds can mimic or block the effect of extracellular calcium on a cell surface calcium receptor.
Inorganic ion receptor activities are those processes brought about as a result of inorganic ion receptor activation. Such processes include the production of molecules which can act as intracellular or extracellular messengers.
Inorganic ion receptor-modulating compounds include ionomimetics, ionolytics, calcimimetics, and calcilytics. Ionomimetics are compounds which mimic (i.e., evoke or potentiate) the effects of an inorganic ion at an inorganic ion receptor. Preferably, the compound affects one or more calcium receptor activities. Calcimimetics are ionomimetics which affect one or more calcium receptor activities.
Ionolytics are compounds which block (i.e., inhibit or diminish) one or more activities caused by an inorganic ion at an inorganic ion receptor. Preferably, the compound affects one or more calcium receptor activities. Calcilytics are ionolytics which block one or more calcium receptor activities evoked by extracellular calcium.
Ionomimetics and ionolytics may bind at the same receptor site as the native inorganic ion ligand binds or can bind at a different site (e.g., an allosteric site). For example, NPS R-467 binding to a calcium receptor results in calcium receptor activity and, thus, NPS R-467 is classified as a calcimimetic. However, NPS R-467 binds to the calcium receptor at a different site (i.e., an allosteric site) than extracellular calcium.
A measure of the effectiveness of a compound to modulate receptor activity can be determined by calculating the EC
50
or IC
50
for that compound. The EC
50
is the concentration of a compound which causes a half-maximal mimicking effect. The IC
50
is the concentration of a compound which causes a half-maximal blocking effect. EC
50
and IC
50
values for compounds at a calcium receptor can be determined by assaying one or more of the activities of extracellular calcium at a calcium receptor. Examples of assays for measuring EC
50
and IC
50
values are described Nemeth et al., PCT/US93/01642, International Publication Number WO 94/18959, and Nemeth et al., PCT/US92/07175, International Publication Number WO 93/04373, (both of these publications are hereby incorporated by reference here) and below. Such assays include oocyte expression assays and measuring increases in intracellular calcium ion concentration ([Ca
2+
]
i
) due to calcium receptor activity. Preferably, such assays measure the release or inhibition of a particular hormone associated with activity of a calcium receptor.
An inorganic ion receptor-modulating compound preferably selectively targets inorganic ion receptor activity in a particular cell. For example, selective targeting of a calcium receptor activity is achieved by a compound exerting a greater effect on a calcium receptor activity in one cell type than at another cell type for a given concentration of compound. Preferably, the differential effect is 10-fold or greater as measured in vivo or in vitro. More preferably, the differential effect is measured in vivo and the compound concentration is measured as the plasma concentration or extracellular fluid concentration and the measured effect is the production of extracellular messengers such as plasma calcitonin, parathyroid hormone, or plasma calcium. For example, in a preferred embodiment, the compound selectively targets PTH secretion over calcitonin secretion.
Preferably, the compound is either a calcimimetic or calcilytic having an EC
50
or an IC
50
at a calcium receptor of less than or equal to 5 &mgr;M, and even more preferably less than or equal to 1 &mgr;M, 100 nmolar, 10 nmolar, or 1 nmolar using one of the assays described below. More preferably, the assay measures intracellular Ca
2+
in HEK 293 cells transformed with nucleic acid expressing the human parathyroid calcium receptor and loaded with fura-2. Lower EC
50
or IC
50
values are advantageous since they allow lower concentrations of compounds to be used in vivo or in vitro. The discovery of compounds with low EC
50
and IC
50
values enables the design and synthesis of additional compounds having similar or improved potency, effectiveness, and/or selectivity.
Thus, a first aspect the invention features an inorganic ion receptor-modulating compound having the formula:
wherein Ar
1
is either optionally substituted naphthyl, optionally substituted phenyl, or an optionally substituted heterocyclic aryl, where up to 5 substituents may be present and each substituent is independently selected from the group consisting of: alkyl, alkenyl, halogen, alkoxy, thioalkyl, methylene dioxy, haloalkyl, haloalkoxy, OH, CH
2
OH, CONH
2
, CN, acetoxy, N(alkyl)
2
, phenyl, phenoxy, benzyl, benzyloxy, &agr;,&agr;-dimethylbenzyl,
Balandrin Manuel F.
DelMar Eric G.
Moe Scott T.
Trovato Richard
Van Wagenen Bradford C.
NPS Pharmaceuticals Inc.
Raymond Richard L.
Warburg Richard J.
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