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1. WO2017034990 - COMPOSITION AND METHODS OF USE OF TETRAHYDROISOQUINOLINE SMALL MOLECULES TO BIND AND MODULATE PCSK9 PROTEIN ACTIVITY

Publication Number WO/2017/034990
Publication Date 02.03.2017
International Application No. PCT/US2016/047798
International Filing Date 19.08.2016
IPC
A61P 3/06 2006.01
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
3Drugs for disorders of the metabolism
06Antihyperlipidemics
A61K 31/472 2006.01
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
33Heterocyclic compounds
395having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
435having six-membered rings with one nitrogen as the only ring hetero atom
47Quinolines; Isoquinolines
472Non-condensed isoquinolines, e.g. papaverine
C07D 217/02 2006.01
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
DHETEROCYCLIC COMPOUNDS
217Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
02with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
CPC
A61K 45/06
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
45Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
A61P 3/06
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
3Drugs for disorders of the metabolism
06Antihyperlipidemics
C07D 217/02
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
DHETEROCYCLIC COMPOUNDS
217Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
02with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
C07D 217/24
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
DHETEROCYCLIC COMPOUNDS
217Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
22with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
24Oxygen atoms
Applicants
  • PORTOLA PHARMACEUTICALS, INC. [US]/[US]
Inventors
  • BARTA, Thomas, E.
  • BOURNE, Jonathan William
  • MONROE, Kyle, D.
  • MUEHLEMANN, Michael, M.
  • PANDEY, Anjali
  • BOWERS, Simeon
Agents
  • SU, Ting
  • KELLY, Gilbert, Thomson
  • CARROLL, Peter, G.
  • HAMDAN, Maha, A.
Priority Data
62/208,06821.08.2015US
Publication Language English (EN)
Filing Language English (EN)
Designated States
Title
(EN) COMPOSITION AND METHODS OF USE OF TETRAHYDROISOQUINOLINE SMALL MOLECULES TO BIND AND MODULATE PCSK9 PROTEIN ACTIVITY
(FR) COMPOSITION ET PROCÉDÉS D'UTILISATION DE PETITES MOLÉCULES DE TYPE TÉTRAHYDROISOQUINOLINE POUR SE LIER À PCSK9 ET MODULER L'ACTIVITÉ PROTÉIQUE DE PCSK9
Abstract
(EN)
This invention is related to the field of PCSK9 biology and the composition and methods of use of small organic compounds as ligands for modulation of PCSK9 biological activity. In particular, the invention provides compositions of small organic compounds that modulate circulating levels of low density lipoproteins by altering the conformation of the protein PCSK9. Binding these small organic compound ligands to PCSK9 alters the conformation of the protein, modifying the interaction between PCSK9 and an endogenous low density lipoprotein receptor, and can lead to reduced or increased levels of circulating LDL-cholesterol. High LDL- cholesterol levels are associated with increased risk for heart disease. Low LDL-cholesterol levels may be problematic in other conditions, such as liver dysfunction; thus, there is also utility for small organic compound ligands that can raise LDL levels.
(FR)
La présente invention relève du domaine de la biologie de PCSK9 et concerne une composition et des procédés d'utilisation de petits composés organiques en tant que ligands pour moduler l'activité biologique de PCSK9. En particulier, l'invention concerne des compositions constituées de petits composés organiques qui modulent les taux circulants de lipoprotéines basse densité par modification de la conformation de la protéine PCSK9. La liaison de ces ligands de type petit composé organique à PCSK9 modifie la conformation de la protéine, modifiant ainsi l'interaction entre la PCSK9 et un récepteur endogène de lipoprotéine basse densité, et permet d'obtenir des taux réduits ou accrus de cholestérol LDL circulant. Des taux élevés de cholestérol LDL sont associés à un risque accru de maladie cardiaque. De bas taux de cholestérol LDL peuvent s'avérer problématiques dans d'autres affections, telles que la dysfonction hépatique; par conséquent, les ligands de type petit composé organique capables d'élever les taux LDL sont également utiles.
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Latest bibliographic data on file with the International Bureau