Praecis Pharmaceuticals, Inc.

New England Deaconess Hospital Corporation

Mark A Findeis

Malcolm L Gefter

Ethan R Signer

Gary Fred Musso

James Wakefield

Kathryn Phillips

Michael Kelley

Howard Benjamin

Susan Molineaux

Joseph Chin

Jung-Ja Lee

Arvind Hundal

Marc B Garnick

Christopher C Arico-Muendel

Laura Kasman

Michael J Reed

Neil J Hayward

Sonja Komar-Panicucci

Robert S Lees

Ann M Lees

Ing-Lung Shih

Allan Fischman

Christopher Self

Gary Olson

David I Israel

William Kubasek

Sonja A Komar

Gary L Olsen

Alicia Peticolas

Farah Natoli

Kuanghui Lu

Martin P Keough

William Goodwin

Ling Chai

Compounds that modulate natural &#x3b2; amyloid peptide aggregation are provided. The modulators of the invention comprise a peptide, preferably based on a &#x3b2; amyloid peptide, that is comprised entirely of D-amino acids. Preferably, the peptide comprises 3-5 D-amino acid residues and includes at least two D-amino acid residues independently selected from the group consisting of D-leucine, D-phenylalanine and D-valine. In a particularly preferred embodiment, the peptide is a retro-inverso isomer of a &#x3b2; amyloid peptide, preferably a retro-inverso isomer of A&#x3b2;. In certain embodiments, the peptide is modified at the amino-terminus, the carboxy-terminus, or both. Preferred amino-terminal modifying groups alkyl groups. Preferred carboxy-terminal modifying groups include an amide group, an acetate group, an alkyl amide group, an aryl amide group or a hydroxy group. Pharmaceutical compositions comprising the compounds of the invention, and diagnostic and treatment methods for amyloidogenic diseases using the compounds of the invention, are also disclosed.

Modulators of &#x3b2;-amyloid peptide aggregation

Compounds that modulate the aggregation of amyloidogenic proteins or peptides are disclosed. The modulators of the invention can promote amyloid aggregation or, more preferably, can inhibit natural amyloid aggregation. In a preferred embodiment, the compounds modulate the aggregation of natural &#x3b2; amyloid peptides (&#x3b2;-AP). In a preferred embodiment, the &#x3b2; amyloid modulator compounds of the invention are comprised of an A&#x3b2; aggregation core domain and a modifying group coupled thereto such that the compound alters the aggregation or inhibits the neurotoxicity of natural &#x3b2; amyloid peptides when contacted with the peptides. Furthermore, the modulators are capable of altering natural &#x3b2;-AP aggregation when the natural &#x3b2;-APs are in a molar excess amount relative to the modulators. Pharmaceutical compositions comprising the compounds of the invention, and diagnostic and treatment methods for amyloidogenic diseases using the compounds of the invention, are also disclosed.

Modulators of amyloid aggregation

Compounds that modulate natural &#x3b2; amyloid peptide aggregation are provided. The modulators of the invention comprise a peptide, preferably based on a &#x3b2; amyloid peptide, that is comprised entirely of D-amino acids. Preferably, the peptide comprises 3&#x2013;5 D-amino acid residues and includes at least two D-amino acid residues independently selected from the group consisting of D-leucine, D-phenylalanine and D-valine. In a particularly preferred embodiment, the peptide is a retro-inverso isomer of a &#x3b2; amyloid peptide, preferably a retro-inverso isomer of A&#x3b2;. In certain embodiments, the peptide is modified at the amino-terminus, the carboxy-terminus, or both. Preferred amino-terminal modifying groups include cyclic, heterocyclic, polycyclic and branched alkyl groups. Preferred carboxy-terminal modifying groups include an amide group, an alkyl amide group, an aryl amide group or a hydroxy group. Pharmaceutical compositions comprising the compounds of the invention, and diagnostic and treatment methods for amyloidogenic diseases using the compounds of the invention, are also disclosed.

Modulators of &#x3b2;-amyloid peptide aggregation comprising D-amino acids

Compounds that modulate natural &bgr; amyloid peptide aggregation are provided. The modulators of the invention comprise a peptide, preferably based on a &bgr; amyloid peptide, that is comprised entirely of D-amino acids. Preferably, the peptide comprises 3-5 D-amino acid residues and includes at least two D-amino acid residues independently selected from the group consisting of D-leucine, D-phenylalanine and D-valine. In a particularly preferred embodiment, the peptide is a retro-inverso isomer of a &bgr; amyloid peptide, preferably a retro-inverso isomer of A&bgr; . In certain embodiments, the peptide is modified at the amino-terminus, the carboxy-terminus, or both. Preferred amino-terminal modifying groups alkyl groups. Preferred carboxy-terminal modifying groups include an amide group, an acetate group, an alkyl amide group, an aryl amide group or a hydroxy group. Pharmaceutical compositions comprising the compounds of the invention, and diagnostic and treatment methods for amyloidogenic diseases using the compounds of the invention, are also disclosed.

Modulators of &bgr;-amyloid peptide aggregation

Compounds that modulate natural &bgr; amyloid peptide aggregation are provided. The modulators of the invention comprise a peptide, preferably based on a &bgr; amyloid peptide, that is comprised entirely of D-amino acids. Preferably, the peptide comprises 3-5 D-amino acid residues and includes at least two D-amino acid residues independently selected from the group consisting of D-leucine, D-phenylalanine and D-valine. In a particularly preferred embodiment, the peptide is a retro-inverso isomer of a &bgr; amyloid peptide, preferably a retro-inverso isomer of A&bgr; . In certain embodiments, the peptide is modified at the amino-terminus, the carboxy-terminus, or both. Preferred amino-terminal modifying groups include cyclic, heterocyclic, polycyclic and branched alkyl groups. Preferred carboxy-terminal modifying groups include an amide group, an alkyl amide group, an aryl amide group or a hydroxy group. Pharmaceutical compositions comprising the compounds of the invention, and diagnostic and treatment methods for amyloidogenic diseases using the compounds of the invention, are also disclosed.

Modulators of &bgr;-amyloid peptide aggregation comprising D-amino acids

Compounds that modulate natural &bgr; amyloid peptide aggregation are provided. The modulators of the invention comprise a peptide, preferably based on a &bgr; amyloid peptide, that is comprised entirely of D-amino acids. Preferably, the peptide comprises 3-5 D-amino acid residues and includes at least two D-amino acid residues independently selected from the group consisting of D-leucine, D-phenylalanine and D-valine. In a particularly preferred embodiment, the peptide is a retro-inverso isomer of a &bgr; amyloid peptide, preferably a retro-inverso isomer of A&bgr; . In certain embodiments, the peptide is modified at the: amino-terminus, carboxy-terminus, or both. Preferred amino-terminal modifying groups alkyl groups. Preferred carboxy-terminal modifying groups include an amide group, an acetate group, an alkyl amide group, an aryl amide group or a hydroxy group. Pharmaceutical compositions comprising the compounds of the invention, and diagnostic and treatment methods for amyloidogenic diseases using the compounds of the invention, are also disclosed.

Modulators of &mgr;-amyloid peptide aggregation

Compounds that modulate the aggregation of amyloidogenic proteins or peptides are disclosed. The modulators of the invention can promote amyloid aggregation or, more preferably, can inhibit natural amyloid aggregation. In a preferred embodiment, the compounds modulate the aggregation of natural &bgr; amyloid peptides (&bgr;-AP). In a preferred embodiment, the &bgr; amyloid modulator compounds of the invention are comprised of an A&bgr; aggregation core domain and a modifying group coupled thereto such that the compound alters the aggregation or inhibits the neurotoxicity of natural &bgr; amyloid peptides when contacted with the peptides. Furthermore, the modulators are capable of altering natural &bgr;-AP aggregation when the natural &bgr;-APs are in a molar excess amount relative to the modulators. Pharmaceutical compositions comprising the compounds of the invention, and diagnostic and treatment methods for amyloidogenic diseases using the compounds of the invention, are also disclosed.

Compounds that modulate natural &bgr; amyloid peptide aggregation are provided. The modulators of the invention comprise a peptide, preferably based on a &bgr; amyloid peptide, that is comprised entirely of D-amino acids. Preferably, the peptide comprises 3-5 D-amino acid residues and includes at least two D-amino acid residues independently selected from the group consisting of D-leucine, D-phenylalanine and D-valine. In a particularly preferred embodiment, the peptide is a retro-inverso isomer of a &bgr; amyloid peptide, preferably a retro-inverso isomer of A&bgr;,. In certain embodiments, the peptide is modified at the amino-terminus, the carboxy-terminus, or both. Preferred amino-terminal modifying groups include cyclic, heterocyclic, polycyclic and branched alkyl groups. Preferred carboxy-terminal modifying groups include an amide group, an alkyl amide group, an aryl amide group or a hydroxy group. Pharmaceutical compositions comprising the compounds of the invention, and diagnostic and treatment methods for amyloidogenic diseases using the compounds of the invention, are also disclosed.

This invention provides peptide compounds that bind to either a fibroblast growth factor (FGF) or a fibroblast growth factor receptor (FGFR) and, accordingly, are useful for modulating FGFR activity. Preferably, the FGFR is FGFR2-IIIC. Preferably, the FGF is basic FGF. Preferably the peptide compound comprises an amino acid sequence: (Y/F)-(L/F/I)-(R/D/E/S/Y/G)-(Q/L/Y)-Y-(M/L/K/R)-(L/M/D/E/N/S)-(R/L/S/T)-(L/F/M/V) (SEQ ID NO: 1). The invention further comprises pharmaceutical compositions comprising the peptide compounds of the invention and a pharmaceutically acceptable carrier. The invention still further provides methods of modulating FGFR activity using the peptide compounds of the invention.

Peptide compounds useful for modulating FGF receptor activity

Compounds that modulate natural .beta. amyloid peptide aggregation are provided. The modulators of the invention comprise a peptide, preferably based on a .beta. amyloid peptide, that is comprised entirely of D-amino acids. Preferably, the peptide comprises 3-5 D-amino acid residues and includes at least two D-amino acid residues independently selected from the group consisting of D-leucine, D-phenylalanine and D-valine. In a particularly preferred embodiment, the peptide is a retro-inverso isomer of a .beta. amyloid peptide, preferably a retro-inverso isomer of A.beta..sub.17-21. In certain embodiments, the peptide is modified at the amino-terminus, the carboxy-terminus, or both. Preferred amino-terminal modifying groups include cyclic, heterocyclic, polycyclic and branched alkyl groups. Preferred carboxy-terminal modifying groups include an amide group, an alkyl amide group, an aryl amide group or a hydroxy group. Pharmaceutical compositions comprising the compounds of the invention, and diagnostic and treatment methods for amyloidogenic diseases using the compounds of the invention, are also disclosed.

Modulators of .beta.-amyloid peptide aggregation comprising D-amino acids

Vascular disease including asymptomatic atherosclerosis can be diagnosed by administering a synthetic peptide or peptide analog having an affinity for, and propensity to accumulate at, a site of vascular injury to a patient, and then detecting the location of the peptide or peptide analog within the patient's vascular system. The synthetic peptide or peptide analog may include an amino acid sequence sufficiently duplicative of the amino acid sequence of a region of either the apolipoprotein B, apolipoprotein A-I, or elastin proteins such that the peptide or peptide analog accumulates at a site of vascular injury.

Synthetic peptides for arterial imaging

Synthetic peptides for arterial imaging at vascular imaging sites

Compounds that modulate the aggregation of amyloidogenic proteins or peptides are disclosed. The modulators of the invention can promote amyloid aggregation or, more preferably, can inhibit natural amyloid aggregation. In a preferred embodiment, the compounds modulate the aggregation of natural .beta. amyloid peptides (.beta.-AP). In a preferred embodiment, the .beta. amyloid modulator compounds of the invention are comprised of an A.beta. aggregation core domain and a modifying group coupled thereto such that the compound alters the aggregation or inhibits the neurotoxicity of natural .beta. amyloid peptides when contacted with the peptides. Furthermore, the modulators are capable of altering natural .beta.-AP aggregation when the natural .beta.-APs are in a molar excess amount relative to the modulators. Pharmaceutical compositions comprising the compounds of the invention, and diagnostic and treatment methods for amyloidogenic diseases using the compounds of the invention, are also disclosed.

A.beta. peptides that modulate .beta.-amyloid aggregation

Compounds that act to modulate the aggregation of natural .beta. amyloid peptides (.beta.-AP) are disclosed. The .beta. amyloid modulators of the invention can promote .beta.-AP aggregation or, more preferably, can inhibit natural .beta.-AP aggregation. Furthermore, the modulators are capable of altering natural .beta.-AP aggregation when the natural .beta.-APs are in a molar excess amount relative to the modulators. Pharmaceutical compositions comprising the compounds of the invention, and methods of altering natural .beta.-AP aggregation using the compounds of the invention, are also disclosed.

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Cambridge, MA, United States of America

Mark A Findeis