Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-04-21
2004-11-23
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C514S013800, C514S014800, C514S015800, C514S016700, C514S017400, C530S317000, C530S323000, C530S324000, C530S325000, C530S326000, C530S327000, C530S328000, C530S329000
Reexamination Certificate
active
06821950
ABSTRACT:
This invention relates to novel cyclic compounds which have the ability to modulate the activity of G protein-coupled receptors. The invention provides both agonists and antagonists. In preferred embodiments, the invention provides cyclic peptidic and cyclic or non-cyclic non-peptidic antagonists or agonists of C5a. The compounds of the invention are both potent and selective, and are useful in the treatment of a variety of inflammatory conditions.
BACKGROUND OF THE INVENTION
Activation of human complement, a system of plasma proteins involved in immunological defence against infection and injury, contributes significantly to the pathogenesis of numerous acute and chronic diseases. In particular, the complement protein C5a has been extensively investigated. For general reviews, see Whaley (1987), and Sim (1993). Table 1 provides a summary of known roles of C5a in disease.
During host defence, the complement system of plasma proteins initiates inflammatory and cellular immune responses to stimuli such as infectious organisms (bacteria, viruses, parasites), chemical or physical injury, radiation or neoplasia. Complement is activated through a complex cascade of interrelated proteolytic events that produce multiple bioactive peptides, some of which (eg. anaphylatoxins C3a and C5a) interact with cellular components to propagate inflammatory processes. Complement activation, either by the classical pathway, after antigen-antibody (Ag/Ab) binding, or by the antibody-independent alternate pathway, ends with a terminal sequence in which protein C5 is proteolytically cleaved by C5 convertase to C5a and C5b. The latter facilitates assembly of a “membrane attack complex” that punches holes in membranes of target cells such as bacteria, leading to leakage, lysis and cell death. Steps in the cascade are tightly regulated to avoid stepwise amplification of proteolysis by sequentially formed proteases. If these regulatory mechanisms become inefficient, protracted activation of complement can result, causing enhanced inflammatory responses as in autoimmune diseases.
Although the broad features of the complement system and its activation are known, mechanistic details remain poorly understood. A principal and very potent mediator of inflammatory responses is the plasma glycoprotein C5a, which interacts with specific surface receptors (C5aR) on mast cells, neutrophils, monocytes, macrophages, non-myeloid cells, and vascular endothelial cells (Gerard and Gerard, 1994). C5aR is a G protein-coupled receptor with seven transmembrane helices (Gerard and Gerard, 1991). This receptor is one of the rhodopsin superfamily of GTP-linked binding proteins, but differs from rhodopsin receptors in that the receptor and G protein are linked prior to activation.
G protein-coupled receptors are prevalent throughout the human body, comprising approximately 80% of known cellular receptor types, and mediate signal transduction across the cell membrane for a very wide range of endogenous ligands. They participate in a diverse array of physiological and pathophysiological processes, including, but not limited to those associated with cardiovascular, central and peripheral nervous system, reproductive, metabolic, digestive, immunoinflammatory, and growth disorders, as well as other cell-regulatory and proliferative disorders. Agents, both agonists and antagonists, which selectively modulate functions of G protein-coupled receptors have important therapeutic applications.
C5a is one of the most potent chemotactic agents known, and recruits neutrophils and macrophages to sites of injury, alters their morphology; induces degranulation; increases calcium mobilisation, vascular permeability (oedema) and neutrophil adhesiveness; contracts smooth muscle; stimulates release of inflammatory mediators (including histamine, TNF-&agr;, IL-1, IL-6, IL-8, prostaglandins, leukotrienes) and lysosomal enzymes; promotes formation of oxygen radicals; and enhances antibody production (Gerard and Gerard, 1994). Overexpresion or underregulation of C5a is implicated in the pathogenesis of immunoinflammatory conditions such as rheumatoid arthritis, adult respiratory distress syndrome (ARDS), systemic lupus erythematosus, tissue graft rejection, ischaemic heart disease, reperfusion injury, septic shock, psoriasis, gingivitis, atherosclerosis, Alzheimer's disease, lung injury and extracorporeal post-dialysis syndrome, and in a variety of other conditions, as summarised in Table 1.
TABLE 1
The Role of C5a in Disease
C5a
C5aR
Condition/disease
levels
expression
Details
allergy
++
allergen challenge leads to
nasal symptoms and
increased C5a levels
Alzheimer's
++
++
up-regulation of the
disease
receptor in reactive astro-
cytes, microglia and endo-
thelial cells in the CNS,
complement system acti-
vated by &bgr;-amyloid
ARDS/respiratory
++
distress
Behcet's disease
++
levels highest just prior to
ocular attacks
bronchial asthma
++
capillary leak
++
syndrome
chronic lung
++
Increased C5a levels in
disease
pulmonary effluent fluid
from mechanically ventil-
ated infants with chronic
lung disease
Churg-Strauss
hypersensitivity of granulo-
cytes to C5a
cystic fibrosis
generation of C5a/effects
on PMNs
decompression
++
increased C5a levels during
stress
saturation diving
diabetes type I
++
C5a generated during onset;
circulating monocytes in
newly diagnosed type 1
diabetes patients are
activated
Familial
lack of C5a inactivator
Mediterranean
fever
Guillain-Barre
++
CSF levels elevated
ischaemic disease
migration of monocytes
states/myocardial
into myocardium after
infarct
reperfusion. Damage
prevented with sCR1
Kimura's disease
humoral factor up-regulates
the response of PMNs to
C5a
Multiple
++
increased expression of
Sclerosis
the receptor on foamy
macrophages in acute and
chronic MS and fibrous
astrocytes in chronic MS
Meningitis
C5a induces experimental
meningitis; PMN accumula-
tion seen in the CSF
pancreatitis
++
post-dialysis
++
−
C5a generated via comple-
syndrome
ment activation by tubing
material, C5aR levels
decreased on PMNs &
monocytes in chronic state
preeclampsia/
++
C5a levels in elevated at
HELLP
delivery
psoriasis
++
C5a levels high in scales
reperfusion injury
++
inhibited by C5 antibody
retinitis
++
C5a detected in vitreous
humor
Rheumatoid
++
elevated concentration of
arthritis
C5a found in synovial fluid
(5-fold) and plasma (3-fold)
Severe congenital
−
neutropenia
transplant/graft
++
monoclonal antibodies
rejection
block the damage seen with
xenogenic transplant;
increased levels of C5a
seen in the plasma and
urine of patients with
renal graft rejection
New agents which limit the pro-inflammatory actions of C5a have potential for inhibiting chronic inflammation, and its accompanying pain and tissue damage. For these reasons, molecules which prevent C5a binding to its receptors are useful for treating chronic inflammatory disorders driven by complement activation. Importantly, such compounds provide valuable new insights to mechanisms of complement-mediated immunity.
In another context, agonists of C5a receptors or other G protein-coupled receptors may also be found to have therapeutic properties in conditions either where the G protein-coupled receptor can be used as a recognition site for drug delivery, or where triggering of such receptors can be used to stimulate some aspect of the human immune system, for example in the treatment of cancers, viral or parasitic infections.
One approach to the development of agonists or antagonists of C5a is through receptor-based design, using knowledge of the three-dimensional structures of C5a, its receptor C5aR, and the interactions between them. The structure of the receptor is unknown. The solution structure of human C5a, a 74 amino acid peptide that is highly cationic and N-glycosylated with a 3 KDa carbohydrate at Asn64, has been determined and is essentially
Fairlie David
Finch Angela Monique
Taylor Stephen Maxwell
Wong Allan
Low Christopher S. F.
Mohamed Abdel A.
The University of Queensland
LandOfFree
Cyclic agonists and antagonists of C5a receptors and G... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Cyclic agonists and antagonists of C5a receptors and G..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Cyclic agonists and antagonists of C5a receptors and G... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3310460