National Research Council of Canada

Université De Sherbrooke

Other

Socpra Sciences Sante Et Humaines S.e.c.

La Societe De Commercialisation Des Produits De La Recherche Appliquee Socpra-Sciences Sante Et Humaines S.e.c.

Societe De Commercialisation Des Produits De La Recheche Appliquee-Socpra-Science Sante Et Humaines S.e.c.

Witold A Neugebauer

James F Whitfield

Gordon E Willick

Fernand Gobeil

Robert Day

Paul Morley

Jean-Rene Barbier

Domenico Regoli

Virginia J Ross

Wing L Sung

Yves Dory

Pierre Sirois

Martin Fugére

David Fortin

Witold Surewicz

Bichov Gabra

Domenico Recoli

Gerard E Plante

Adriana Zucollo

Martin Fugère

Orlando L Catanzaro

Martin Fugere

It is provided PACE4 inhibitors and their uses for treating infection, cancer. Particularly, it is provided a method or use for the treatment of a cancer in a subject, comprising administering to the subject a therapeutically effective amount of the PACE4 inhibitors or the composition disclosed.

Stable peptide-based PACE4 inhibitors

Disclosed herein are PACE4 inhibitors, compositions comprising PACE4 inhibitors and their uses thereof for lowering PACE4 activity, reducing cell proliferation, reducing tumor growth, reducing metastasis formation, preventing and/or treating cancer. Also provided are methods for lowering PACE4 activity, reducing the proliferation of a cell, reducing tumor growth and/or treating and preventing cancer. Methods for screening PACE4 inhibitors and cell proliferation inhibitors are further provided.

Multi-leu peptides and analogues thereof as selective PACE4 inhibitors and effective antiproliferative agents

Multi-LEU peptides and analogues thereof as selective PACE4 inhibitors and effective antiproliferative agents

The present invention provides for novel kinin B1 receptors peptide agonists of formula (I) having very good to excellent affinities and selectivity for the Breceptor, in vitro and in vivo increased resistance to enzymatic degradation, superior pharmacokinetic properties to those of naturally occurring agents, capacity to significantly enhance delivery of chemotherapeutic substances across the blood brain barrier and within peripheral tissues for the treatment of tumors, capacity to protect and restore kidney, heart, brain and other organ functions, when given alone or in combination with other therapies in the treatment of hypertension, diabetes and other cardiovascular diseases particularly, but not limited to, atherosclerosis and arteriosclerosis. Formula (I): aa-aa-aa-aa-aa-aa-aa-aa-Ser-Pro-D-Phe-X.

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The present invention provides for a novel peptidic antagonist for the bradykinin B1 (BKB) receptor having very good to excellent affinities and selectivity for the BKBreceptor, in vitro and in vivo increase resistance to enzymatic degradation, superior pharmacokinetic properties, capability to significantly reduce microvascular leakage observed alongside diabetic-induced increase in vascular permeability, capability to significantly reduced the state of hyperalgesia alongside diabetes, capability to significantly reduce the infiltration of pro-inflammatory cells and general state of inflammation alongside allergic asthma.

Selective bradykinin (BK) B1 peptidic receptor antagonists and uses thereof

The present invention relates to novel antagonists to a B-bradykinin (B-BK) receptor which have a good affinity and selectivity therefor, some of which being at least partially resistant to enzymatic degradation. The synthesis of the Breceptors is induced during inflammation. Symptoms associated with inflammation (elevated hydrostatic pressure and plasma leakage or extravasation) have been observed in diabetic animal models (streptozotocin-induced diabetes (STZ)) as well as in spontaneously hypertensive rats (SHR). The present inventors confirm the presence of B-BK receptors in these two models. B-BK antagonists abolished the vasocontraction induced by B-BK in SHR and STZ, and reduced the glycemia of diabetic animals to normal levels. The present B-antagonists are useful for treating any condition wherein B-receptor is expressed, particularly during inflammation, and more particularly wherein B-receptor expression results in diabetic vasculopathy, other diabetic symptoms associated with an insulitis and a post-capillary resistance building as a consequence of the presence of a B-receptor.

This invention describes analogues of human parathyroid hormone which have increased activities in bone restoration, and increased bioavailability. The peptides described are derivatives of hPTH-(1-31) which are cyclized for example, by formation of lactams between either Glu and Lys or Lys and Asp . In addition, the natural Lys may be substituted by either a Leu or other hydrophobic residues, such as Ile, norleucine, Met, Val, Ala, Trp, or Phe. Typically, these analogues have enhanced abilities to stimulate adenylyl cyclase in rat osteosarcoma cells, and show increased activities in bone restoration, using the ovariectomized rat model. The analogues also show enhanced activities and bioavailabilities, as demonstrated by their hypotensive effects in the rat. An assay which correlates hypotensive activity with osteogenic activity is also described.

Parathyroid hormone analogues for the treatment of osteoporosis

This invention describes analogues of human parathyroid hormone which have increased activities in bone restoration, and increased bioavailabilities. The peptides described are derivatives of hPTH-(1-31) which are cyclized for example, by formation of lactams between either Glu.sup.22 and Lys.sup.26 or Lys.sup.26 and Asp.sup.30. In addition, the natural Lys.sup.27 may be substituted by either a Leu or other hydrophobic residues, such as Ile, norleucine, Met, Val, Ala, Trp, or Phe. Typically, these analogues have enhanced abilities to stimulate adenylyl cyclase in rat osteosarcoma cells, and show increased activities in bone restoration, using the ovariectomized rat model. The analogues also show enhanced activities and bioavailabilities, as demonstrated by their hypotensive effects in the rat. An assay which correlates hypotensive activity with osteogenic activity is also described.

This invention describes analogs of human parathyroid hormone which have increased activities in bone restoration, and increased bioavailabilities. The peptides described are derivatives of hPTH-(1-31) which have lactams formed for example, between either Glu.sup.22 and Lys.sup.26 or Lys.sup.26 and Asp.sup.30. In addition, the natural Lys.sup.27 may be substituted by either a Leu or other hydrophobic residues, such as Ile, norleucine, Met, Val, Ala, Trp, or Phe. Typically, these analogs have enhanced abilities to stimulate adenylyl cyclase in rat osteosarcoma cells, and show increased activities in bone restoration, using the ovariectomized rat model. The analogs also show enhanced activities and bioavailabilities, as demonstrated by their hypotensive effects in the rat.

Certain analogues of human parathyroid hormone (hPTH) have been found to be effective for the treatment of osteoporosis, while showing decreased side effects. Analogues showing this effect include all sequences from hPTH-(1-28)-NH.sub.2 to hPTH-(1-31)-NH.sub.2 and all sequences from [Leu.sup.27 ]-hPTH-(1-28)-NH.sub.2 to [Leu.sup.27 ]-hPTH-(1-33)-NH.sub.2. Also included are cyclic analogues cyclo(Lys.sup.26 -Asp.sup.30) [Leu.sup.27 ]-hPTH-(1-34)NH.sub.2 and cyclo (Lys.sup.27 -Asp.sup.30 )-hPTH-(1-34)-NH.sub.2. Analogues in the form of the carboxyl terminal amide are particularly effective.

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Ottawa, Canada

Witold A Neugebauer