- Highly stereoselective one-pot construction of trisubstituted tetrahydro-β-carboline-fused diketopiperazines: A synthetic route towards cialis analogues
-
A facile and efficient synthetic method for the stereoselective preparation of trisubstituted tetrahydro-β-carboline-fused diketopiperazine derivatives is reported. The methodology represents a one-pot four-step reaction, employing the Ugi four-component
- Jida, Mouhamad,Tourwe, Dirk,Ballet, Steven
-
p. 38159 - 38163
(2014/11/08)
-
- Drug-to-genome-to-drug, step 2: Reversing selectivity in a series of antiplasmodial compounds
-
In a recent paper, we have described the discovery of antimalarial compounds derived from tadalafil, using a drug-to-genome-to-drug approach (J. Med. Chem. 2011, 54 (9), pp 3222-3240). We have shown that these derivatives inhibit the phosphodiesterase activity of Plasmodium falciparum and the parasite growth in culture. In this paper, we describe the optimization of these compounds. A direct consequence of our approach based on gene orthology is the lack of selectivity of the compounds over the original activity on the human target. We demonstrate here that it is possible to take advantage of subtle differences in SAR between HsPDE5 inhibition and antiplasmodial activity to improve significantly the selectivity. In particular, the replacement of the piperonyl group in compound 2 by a dimethoxyphenyl group was the best way to optimize selectivity. This observation is consistent with the differences between human and plasmodial sequences in the Q2 pocket receiving this group.
- Beghyn, Terence B.,Charton, Julie,Leroux, Florence,Henninot, Antoine,Reboule, Irena,Cos, Paul,Maes, Louis,Deprez, Benoit
-
experimental part
p. 1274 - 1286
(2012/04/04)
-
- First highly stereocontrolled synthesis of tetrahydro trans-β- carboline derivatives by exploiting the influence of a cyclic amide
-
Stereocontrolled synthesis of trans-β-carboline derivatives by employing amidation strategy is presented. ARKAT-USA, Inc.
- Vedantham, Ravindra,Shanmugam, Sakthivel,Vetukuri, Prasadaraju Vnkv,Khagga, Mukkanti,Bandichhor, Rakeshwar
-
-
- Synthesis and evaluation of human phosphodiesterases (PDE) 5 inhibitor analogs as trypanosomal PDE inhibitors. Part 2. Tadalafil analogs
-
In this Letter we describe our ongoing target repurposing efforts focused on discovery of inhibitors of the essential trypanosomal phosphodiesterase TbrPDEB1. This enzyme has been implicated in virulence of Trypanosoma brucei, the causative agent of human African trypanosomiasis (HAT). We outline the synthesis and biological evaluation of analogs of tadalafil, a human PDE5 inhibitor currently utilized for treatment of erectile dysfunction, and report that these analogs are weak inhibitors of TbrPDEB1.
- Ochiana, Stefan O.,Gustafson, Alden,Bland, Nicholas D.,Wang, Cuihua,Russo, Michael J.,Campbell, Robert K.,Pollastri, Michael P.
-
scheme or table
p. 2582 - 2584
(2012/05/05)
-
- An efficient and general method for the stereodivergent syntheses of tadalafil-like tetracyclic compounds
-
A clean and general DBU-catalyzed epimerization at C-12a position of the tadalafil-like tetracyclic compounds has been fully studied. In addition, by using this clean epimerization as the key step, four stereomers of 6-d 1-tadalafil were stereodivergently synthesized from, both L- and D-tryptophan methyl ester hydrochlorides and deuterated piperonal.
- Xiao, Sen,Shi, Xiao-Xin,Ni, Feng,Xing, Jing,Yan, Jing-Jing,Liu, Shi-Ling
-
experimental part
p. 1711 - 1716
(2010/05/19)
-
- Microwave-assisted synthesis of tetracyclic 2,5-diketopiperazines on a soluble polymer support: A structural analogue of tadalafil
-
Structural analogues of tadalafil that contain two diversity points have been synthesized from a soluble polymer support employing a PictetSpengler reaction using focussed microwave irradiation. Polymer-bound deprotected tryptophan reacts with various ald
- Chang, Wong-Jin,Chanda, Kaushik,Sun, Chung-Ming
-
experimental part
p. 42 - 50
(2009/07/25)
-
- Two Concise syntheses of cialis via the N-acyliminium pictet-spengler reaction
-
The imine derived from piperonal and D-tryptophan methyl ester underwent N-acyliminium Pictet-Spengler reaction with either Fmoc-sarcosyl chloride or chloroacetyl chloride. The products were readily converted to the drug Cialis.
- Revell, Jefferson D.,Srinivasan, Natarajan,Ganesan
-
p. 1428 - 1430
(2007/10/03)
-
- Synthesis and SAR of tetracyclic pyrroloquinolones as phosphodiesterase 5 inhibitors
-
The synthesis of the fused tetracyclic pyrroloquinolones 9a-i in four steps is described. The PDE5 inhibitory activities of these compounds, their selectivities against PDE1, PDE2, PDE3, PDE4 and PDE6, the preclinical pharmacokinetic assessments and the in vivo efficacy in increasing intracavernosal pressure are presented and discussed.
- Jiang, Weiqin,Alford, Vernon C.,Qiu, Yuhong,Bhattacharjee, Sheela,John, T. Matthew,Haynes-Johnson, Donna,Kraft, Patricia J.,Lundeen, Scott G.,Sui, Zhihua
-
p. 1505 - 1515
(2007/10/03)
-
- 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
-
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
-
p. 4533 - 4542
(2007/10/03)
-
- Method of inhibiting neoplastic cells with tetracyclic pyrido[3,4-B] indole derivatives
-
A method for inhibiting neoplasia, particularly cancerous and precancerous lesions by exposing the affected cells to pyrido[3,4b]indoles.
- -
-
-