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1. (WO2016203402) BIS-FURAN DERIVATIVES AS TRANSTHYRETIN (TTR) STABILIZERS AND AMYLOID INHIBITORS FOR THE TREATMENT OF FAMILIAL AMYLOID POLYNEUROPATHY (FAP)
Latest bibliographic data on file with the International Bureau   

Pub. No.: WO/2016/203402 International Application No.: PCT/IB2016/053546
Publication Date: 22.12.2016 International Filing Date: 15.06.2016
IPC:
C07D 307/68 (2006.01) ,A61K 31/341 (2006.01) ,A61P 25/28 (2006.01)
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
D
HETEROCYCLIC COMPOUNDS
307
Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
02
not condensed with other rings
34
having two or three double bonds between ring members or between ring members and non-ring members
56
with 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 ring carbon atoms
68
Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31
Medicinal preparations containing organic active ingredients
33
Heterocyclic compounds
335
having oxygen as the only ring hetero atom, e.g. fungichromin
34
having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
341
not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
P
SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
25
Drugs for disorders of the nervous system
28
for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Applicants:
BSIM2 – BIOMOLECULAR SIMULATIONS, S.A. [PT/PT]; Biocant Park, Parque Tecnológico de Cantanhede, Núcleo 04, Lote 2 3060-197 Cantanhede, PT
Inventors:
VIEIRA SIMÕES, Carlos José; PT
LOURENÇO DE ALMEIDA, Zaida Catarina; PT
VASCONCELOS DIAS DE PINHO E MELO, Teresa Margarida; PT
PONTES MEIRELES FERREIRA DE BRITO, Rui Manuel; PT
SILVA COSTA, Dora Cristina; PT
CABRAL CARDOSO LOPES, Ana Lúcia; PT
Agent:
TEIXEIRA DE CARVALHO, Anabela; PT
Priority Data:
10944209.06.2016PT
62/180,03615.06.2015US
62/204,34612.08.2015US
Title (EN) BIS-FURAN DERIVATIVES AS TRANSTHYRETIN (TTR) STABILIZERS AND AMYLOID INHIBITORS FOR THE TREATMENT OF FAMILIAL AMYLOID POLYNEUROPATHY (FAP)
(FR) DÉRIVÉS DE BIS-FURANE EN TANT QUE STABILISATEURS DE LA TRANSTHYRÉTINE (TTR) ET INHIBITEURS D'AMYLOÏDE POUR LE TRAITEMENT DE LA POLYNEUROPATHIE AMYLOÏDE FAMILIALE (FAP)
Abstract:
(EN) The design and synthesis of a novel bis-furan scaffold tailored for high efficiency at inhibiting transthyretin amyloid formation is reported. In vitro results show that the discovered compounds are more efficient inhibitors of amyloid formation than tafamidis, a drug currently used in the treatment of familial amyloid polyneuropathy (FAP), despite their lower molecular weight and lipophilicity. Moreover, ex vivo experiments with the strongest inhibitor in the series, conducted in human blood plasma from normal and FAP Val30Met-transthyretin carriers, disclose remarkable affinity and selectivity profiles. The promises and challenges facing further development of this compound are discussed under the light of increasing evidence implicating transthyretin stability as a key factor not only in transthyretin amyloidoses and several associated co-morbidities, but also in Alzheimer's disease.
(FR) La présente invention concerne la conception et la synthèse d'un nouvel échafaudage bis-furane conçu pour inhiber avec une efficacité élevée la formation d'amyloïdes à partir de la transthyrétine. Des résultats in vitro montrent que les composés découverts sont des inhibiteurs plus efficaces de formation d'amyloïdes que le tafamidis, un médicament actuellement utilisé dans le traitement de la polyneuropathie amyloïde familiale (FAP), malgré leur poids moléculaire inférieur et leur caractère lipophile. De plus, des expériences ex vivo avec l'inhibiteur le plus puissant de la série, réalisées sur du plasma sanguin humain par rapport à des vecteurs normaux et de FAP Val30Met-transthyrétine, montrent des profils d'affinité et de sélectivité remarquables. Les défis et les promesses du développement plus avant de ce composé sont présentés à la lumière d'un nombre croissant de preuves impliquant la stabilité de la transthyrétine en tant que facteur clé dans des amyloïdoses à transthyrétine et de plusieurs co-morbidités associées, mais également dans la maladie d'Alzheimer.
Designated States: AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW
African Regional Intellectual Property Organization (ARIPO) (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW)
Eurasian Patent Office (AM, AZ, BY, KG, KZ, RU, TJ, TM)
European Patent Office (EPO) (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR)
African Intellectual Property Organization (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG)
Publication Language: English (EN)
Filing Language: English (EN)