- Impact of Scaffold Exploration on Novel Dual-Acting Histone Deacetylases and Phosphodiesterase 5 Inhibitors for the Treatment of Alzheimer’s Disease
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A novel systems therapeutics approach, involving simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylase (HDAC), has been validated as a potentially novel therapeutic strategy for the treatment of Alzheimer’s disease (AD). First-in-class dual inhibitors bearing a sildenafil core have been very recently reported, and the lead molecule 7 has proven this strategy in AD animal models. Because scaffolds may play a critical role in primary activities and ADME-Tox profiling as well as on intellectual property, we have explored alternative scaffolds (vardenafil- and tadalafil-based cores) and evaluated their impact on critical parameters such as primary activities, permeability, toxicity, and in vivo (pharmacokinetics and functional response in hippocampus) to identify a potential alternative lead molecule bearing a different chemotype for in vivo testing.
- Sánchez-Arias, Juan A.,Rabal, Obdulia,Cuadrado-Tejedor, Mar,De Miguel, Irene,Pérez-González, Marta,Ugarte, Ana,Sáez, Elena,Espelosin, Maria,Ursua, Susana,Haizhong, Tan,Wei, Wu,Musheng, Xu,Garcia-Osta, Ana,Oyarzabal, Julen
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p. 638 - 661
(2017/03/20)
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- Drug to genome to drug: Discovery of new antiplasmodial compounds
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Figure Presented. The dominant strategy for discovery of new antimalarial drugs relies on cell-free assays on specific biochemical pathways of Plasmodium falciparum. However, it appears that screening directly on the parasite is a more rewarding approach. The drug to genome to drug approach consists of testing a small set of structural analogues of a drug acting on human proteins that have plasmodial orthologues. Both man and plasmodium possess cyclic nucleotide phosphodiesterases (PDEs) that are key players of cell homeostasis. We synthesized and tested 40 analogues of tadalafil, a human PDE5 inhibitor, on P. falciparum in culture and obtained potent inhibitors of parasite growth. We discuss the structure-activity relationships, which support the hypothesis that our compounds kill the parasite via inhibition of plasmodial PDE activity. We also prove that antiplasmodial derivatives inhibit the hydrolysis of cyclic nucleotides of the parasite, validating the cAMP/cGMP pathways as therapeutic targets against Plasmodium falciparum.
- Beghyn, Terence B.,Charton, Julie,Leroux, Florence,Laconde, Guillaume,Bourin, Arnaud,Cos, Paul,Maes, Louis,Deprez, Benoit
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p. 3222 - 3240
(2011/06/27)
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- PDE5 inhibitors: An original access to novel potent arylated analogues of tadalafil
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A method to access totally new analogues of tadalafil was explored. The Buchwald reaction was adapted and used to replace the methyl group of tadalafil by various aryl groups. Inhibition potencies on PDE5 of these analogues were determined and proved to be comparable to the one of tadalafil. Using the same route, compounds with the same level of activity but improved water solubility were produced by introducing a pyridine or a pyrimidine ring. This original route also opens access to new unpatented compounds.
- Beghyn, Terence,Hounsou, Candide,Deprez, Benoit P.
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p. 789 - 792
(2007/10/03)
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- The discovery of tadalafil: A novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-Hexahydropyrazino[1′,2′ :1,6]pyrido[3,4-b]indole-1,4-dione analogues
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Modification of the hydantoin ring in the previously described lead compound 2a has led to the discovery of compound 12a, tadalafil, a highly potent and highly selective PDE5 inhibitor. The replacement of the hydantoin in compound 2a by a piperazinedione ring led to compound cis-11a which showed similar PDE5 inhibitory potency. Introduction of a 3,4-methylenedioxy substitution on the phenyl ring in position 6 led to a potent PDE5 inhibitor cis-11c with increased cellular potency. Optimization of the chain on the piperazinedione ring led to the identification of the racemic cis-N-methyl derivative 11i. High diastereospecificity for PDE5 inhibition was observed in the piperazinedione series with the cis-(6R,12aR) enantiomer displaying the highest PDE5 inhibitory activity. The piperazinedione 12a, tadalafil (GF196960), has been identified as a highly potent PDE5 inhibitor (IC50 = 5 nM) with high selectivity for PDE5 vs PDE1-4 and PDE6. Compound 12a displays 85-fold greater selectivity vs PDE6 than sildenafil 1. 12a showed profound and long-lasting blood pressure lowering activity (30 mmHg/>7 h) in the spontaneously hypertensive rat model after oral administration (5 mg/kg).
- Daugan, Alain,Grondin, Pascal,Ruault, Cécile,Le Monnier de Gouville, Anne-Charlotte,Coste, Hervé,Linget, Jean Michel,Kirilovsky, Jorge,Hyafil, Fran?ois,Labaudinièret, Richard
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p. 4533 - 4542
(2007/10/03)
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- Method of treating nitrate-induced tolerance
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The present invention relates to methods for treating nitrate-induced tolerance in a mammal by administering a nitrate-induced tolerance treating amount of a compound of formulae (I), (II), (III) (IV), (V), (VI), (VII), (VIII), (IX), (XA) or (XB) as defined herein, or the pharmaceutically acceptable salts, prodrugs, polymorphs, hydrates, solvates, active metabolites or stereoisomers thereof. The invention also relates to pharmaceutical compositions for the treatment of nitrate-induced tolerance in a mammal comprising a nitrate-induced tolerance treating amount of a compound of formulae (I), (II), (III) (IV), (V), (VI), (VII), (VIII), (IX), (XA) or (XB) as defined herein, or the pharmaceutically acceptable salts, prodrugs, polymorphs, hydrates, solvates, active metabolites or stereoisomers thereof, and a pharmaceutically acceptable vehicle, diluent or carrier. The invention further relates to methods of preventing nitrate-induced tolerance in a mammal comprising administering a nitrate-induced tolerance preventing amount of a cGMP PDE inhibitor.
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