Aptiganel
(преусмерено са ARL-16247)
Aptiganel (Cerestat; CNS-1102) je neuspešan kandidat za lek koji deluje kao nekonkurentni antagonist NMDA, a koji je razvijala kompanija Cambridge Neuroscience, Inc kao tretman za moždani udar.[1] On ima neuroprotektivne efekte i istraživan je za potencijalnu upotrebu u lečenju moždanog udara,[2] ali uprkos pozitivnim rezultatima u studijama na životinjama,[3] ispitivanja na ljudima su pokazala ograničenu efikasnost,[4] kao i neželjene nuspojave kao što su sedacija i halucinacije,[5][6] i klinički razvoj ultimatno nije nastavljen.[7]
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| Klinički podaci | |
|---|---|
| Drugs.com | Monografija |
| Identifikatori | |
| CAS broj | 137159-92-3  |
| ATC kod | none |
| PubChem | CID 60840 |
| ChemSpider | 54827 |
| UNII | 46475LV84I |
| ChEMBL | CHEMBL92484 |
| Hemijski podaci | |
| Formula | C20H21N3 |
| Molarna masa | 303,401 |
| |
| |
Neuspeh ovog leka doveo je do kolapsa preduzeća Kembridž neuronauka 1998.[8] i njegove prodaje firmi CeNeS Farmaceutikals 2000. godine.[9]
Druge gvanidinske supstance na kojima je kompanija vršila testove bile su Cns-1145 i CNS1237.
Sinteza
уреди
1-Naftilamin reaguje sa cijanogen bromidom da bi se dobilo jedinjenje 2. Tretman ovog intermedijera sa 3-etil-N-metilanilinom dovodi do dodavanja cijano grupe i formiranja odgovarajućeg diaril gvanidina, aptiganela, 3.
Osobine
уредиAptiganel je organsko jedinjenje, koje sadrži 20 atoma ugljenika i ima molekulsku masu od 303,401 Da.
| Osobina | Vrednost |
|---|---|
| Broj akceptora vodonika | 1 |
| Broj donora vodonika | 2 |
| Broj rotacionih veza | 5 |
| Particioni koeficijent[12] (ALogP) | 4,6 |
| Rastvorljivost[13] (logS, log(mol/L)) | -5,0 |
| Polarna površina[14] (PSA, Å2) | 39,1 |
Reference
уреди- ^ Reddy NL, Hu LY, Cotter RE, Fischer JB, Wong WJ, McBurney RN, et al. (јануар 1994). „Synthesis and structure-activity studies of N,N'-diarylguanidine derivatives. N-(1-naphthyl)-N'-(3-ethylphenyl)-N'-methylguanidine: a new, selective noncompetitive NMDA receptor antagonist”. Journal of Medicinal Chemistry. 37 (2): 260—7. PMID 8295213. doi:10.1021/jm00028a009.
- ^ Muir KW, Grosset DG, Gamzu E, Lees KR (јул 1994). „Pharmacological effects of the non-competitive NMDA antagonist CNS 1102 in normal volunteers”. British Journal of Clinical Pharmacology. 38 (1): 33—8. PMC 1364834
. PMID 7946934. doi:10.1111/j.1365-2125.1994.tb04318.x.
- ^ Schäbitz WR, Li F, Fisher M (јул 2000). „The N-methyl-D-aspartate antagonist CNS 1102 protects cerebral gray and white matter from ischemic injury following temporary focal ischemia in rats”. Stroke. 31 (7): 1709—14. PMID 10884477. doi:10.1161/01.str.31.7.1709 .
- ^ Albers GW, Goldstein LB, Hall D, Lesko LM (децембар 2001). „Aptiganel hydrochloride in acute ischemic stroke: a randomized controlled trial”. JAMA. 286 (21): 2673—82. PMID 11730442. doi:10.1001/jama.286.21.2673.
- ^ Muir KW, Grosset DG, Lees KR (август 1997). „Effects of prolonged infusions of the NMDA antagonist aptiganel hydrochloride (CNS 1102) in normal volunteers”. Clinical Neuropharmacology. 20 (4): 311—21. PMID 9260729. doi:10.1097/00002826-199708000-00003.
- ^ Lees KR (новембар 1997). „Cerestat and other NMDA antagonists in ischemic stroke”. Neurology. 49 (5 Suppl 4): S66—9. PMID 9371155. S2CID 45771202. doi:10.1212/wnl.49.5_suppl_4.s66.
- ^ Hoyte L, Barber PA, Buchan AM, Hill MD (март 2004). „The rise and fall of NMDA antagonists for ischemic stroke”. Current Molecular Medicine. 4 (2): 131—6. PMID 15032709. doi:10.2174/1566524043479248.
- ^ Staff, Boston Business Journal. May 7, 1998. CNSI appoints new president, CEO
- ^ Staff, ICIS. 23 May 2000 CeNeS to buy US neuroscience firm CNSI for $44m
- ^ Reddy NL, Hu LY, Cotter RE, Fischer JB, Wong WJ, McBurney RN, et al. (јануар 1994). „Synthesis and structure-activity studies of N,N'-diarylguanidine derivatives. N-(1-naphthyl)-N'-(3-ethylphenyl)-N'-methylguanidine: a new, selective noncompetitive NMDA receptor antagonist”. Journal of Medicinal Chemistry. 37 (2): 260—7. PMID 8295213. doi:10.1021/jm00028a009.
- ^ WO 9112797, Weber, Eckard & Keana, John F. W., "Tri- and tetra-substituted guanidines and their use as excitatory amino acid antagonists", published 1991-09-05, assigned to University of Oregon and Oregon Health Sciences University; E. Weber, J. F. W. Keana, U.S. Patent 5.262.568 (1993 to State of Oregon)
- ^ Ghose, A.K.; Viswanadhan V.N. & Wendoloski, J.J. (1998). „Prediction of Hydrophobic (Lipophilic) Properties of Small Organic Molecules Using Fragment Methods: An Analysis of AlogP and CLogP Methods”. J. Phys. Chem. A. 102: 3762—3772. doi:10.1021/jp980230o.
- ^ Tetko IV, Tanchuk VY, Kasheva TN, Villa AE (2001). „Estimation of Aqueous Solubility of Chemical Compounds Using E-State Indices”. Chem Inf. Comput. Sci. 41: 1488—1493. PMID 11749573. doi:10.1021/ci000392t.
- ^ Ertl P.; Rohde B.; Selzer P. (2000). „Fast calculation of molecular polar surface area as a sum of fragment based contributions and its application to the prediction of drug transport properties”. J. Med. Chem. 43: 3714—3717. PMID 11020286. doi:10.1021/jm000942e.
Literatura
уреди- Hardman JG, Limbird LE, Gilman AG (2001). Goodman & Gilman's The Pharmacological Basis of Therapeutics (10. изд.). New York: McGraw-Hill. ISBN 0071354697. doi:10.1036/0071422803.
- Thomas L. Lemke; David A. Williams, ур. (2007). Foye's Principles of Medicinal Chemistry (6. изд.). Baltimore: Lippincott Willams & Wilkins. ISBN 0781768799.
