Comparison of different heterocyclic scaffolds as substrate analog PDE5 inhibitors

Haning, Helmut; Niewöhner, Ulrich; Schenke, Thomas; Lampe, Thomas; Hillisch, Alexander; Bischoff, Erwin

doi:10.1016/j.bmcl.2005.05.090

Cited by 42 publications

(27 citation statements)

References 21 publications

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“…In a very interesting study, Haning et al [28] compared several different heterocyclic systems as PDE5 inhibitor scaffolds. In addition to the known 3H-imidazo[5, 1-f] [1,2,4]triazin-4-ones and pyrazolopyrimidinones, present in the clinically used compounds discussed above, the isomeric imidazo/isoxazolo[1, 5-a] [1,3,5]triazin-4(3H)-ones were also shown to be potent and selective PDE inhibitor scaffolds with in vivo activity.…”

Section: Drug Design Of Pde5ismentioning

confidence: 99%

Phosphodiesterase 5 Inhibitors - Drug Design and Differentiation Based on Selectivity, Pharmacokinetic and Efficacy Profiles

Supuran¹,

Mastrolorenzo²,

Bárbaro³

et al. 2006

CPD

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The discovery that inhibition of phosphodiesterase-5 (PDE5) reduces the degradation of cGMP, allowing erectile function to occur by relaxation of penile smooth muscle, represents a revolutionary approach or the treatment of erectile dysfunction (ED). Three PDE5 inhibitors (sildenafil, tadalafil, and vardenafil) are clinically available at this time, and extensive drug design efforts are registered for finding agents with a better activity, enhanced selectivity and reduced side effects. Many classes of such compounds have been reported, belonging to diverse chemical entities. The drug design has been very much facilitated after the report of the X-ray crystal structure of the PDE5 catalytic domain in complex with the three clinically used derivatives. PDE5 inhibitor therapy, has been found to be effective in special clinical populations, such as those with prostate cancer, diabetes, and cardiovascular disease. The duration of action of sildenafil and vardenafil is of about 4 hours, whereas that of tadalafil is of about 36 hours, and the overall safety of the treatments is good. There is a risk of hypotension if nitrates are given concurrently with the PDE5 inhibitors. Common side-effects include headache, facial flushing, nasal congestion, dyspepsia and transient visual impairment. There are pharmacological interactions between these drugs and other medications metabolized by the cytochrome P450 (P3A4 isoform), such as the azole antifungals, erythromycin and the HIV protease inhibitors.

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Section: Drug Design Of Pde5ismentioning

confidence: 99%

Phosphodiesterase 5 Inhibitors - Drug Design and Differentiation Based on Selectivity, Pharmacokinetic and Efficacy Profiles

Supuran¹,

Mastrolorenzo²,

Bárbaro³

et al. 2006

CPD

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“…However,the higherbiochemical potencyofvardenafil over sildenafilh as been largely attributed to the successful scaffold leap to the different heterocyclic core. [50] To gain further insighti nto the SAR at the piperazine position and to investigate possible implications on the in vitro pharmacokinetic properties, the sulfoximine analogue 29 of vardenafil was prepared in an opportunistic approach. The synthesis of sulfoximine analogue 29 was accomplished in just two steps.…”

Section: Vardenafilmentioning

confidence: 99%

Novel Pieces for the Emerging Picture of Sulfoximines in Drug Discovery: Synthesis and Evaluation of Sulfoximine Analogues of Marketed Drugs and Advanced Clinical Candidates

2017

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Sulfoximines have gained considerable recognition as an important structural motif in drug discovery of late. In particular, the clinical kinase inhibitors for the treatment of cancer, roniciclib (pan‐CDK inhibitor), BAY 1143572 (P‐TEFb inhibitor), and AZD 6738 (ATR inhibitor), have recently drawn considerable attention. Whilst the interest in this underrepresented functional group in drug discovery is clearly on the rise, there remains an incomplete understanding of the medicinal‐chemistry‐relevant properties of sulfoximines. Herein we report the synthesis and in vitro characterization of a variety of sulfoximine analogues of marketed drugs and advanced clinical candidates to gain a better understanding of this neglected functional group and its potential in drug discovery.

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“…In continuation of this work and in the course of program directed toward the synthesis of novel pyrazolo[4,3‐ d ]pyrimidine derivatives, we choose 4‐amino‐1‐methyl‐3‐propyl‐1 H ‐pyrazole‐5‐carboxamide 1 as a substrate. Compound 1 was synthesized by literature procedure . The regioselective condensation reaction of p ‐chlorobenzaldehyde with o ‐amino carboxamide 1 in the presence of acetonitrile and slight excess of molecular iodine furnished pyrazolopyrimidine 2 in quantitative yield (82%) .…”

Section: Introductionmentioning

confidence: 99%

A Convenient Synthesis of New Pyrazolo[4,3‐d]pyrimidines and Their Fused Heterocycles

Rote

Shelar

Patil

et al. 2013

Journal of Heterocyclic Chem

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A series of some fused heterocycles originated from pyrazolopyrimidines were synthesized using 4‐amino1‐methyl‐3‐propyl‐1H‐pyrazole‐5‐carboxamide as a starting material. The nucleophilic substitution reactions with different amino acids followed by cyclization and Suzuki–Miyaura cross‐coupling reactions with different aryl boronic acids of 7‐chloro‐5‐(4‐chlorophenyl)‐1‐methyl‐3‐propyl‐1H‐pyrazolo[4,3‐d]pyrimidine were performed. Also, the oxidative cyclization reactions of 1‐(5‐(4‐chlorophenyl)‐1‐methyl‐3‐propyl‐1H‐pyrazolo[4,3‐d]pyrimidin‐7‐yl)hydrazine with different aldehydes in the presence of diacetoxy iodobenzene are described. All the synthesized compounds were characterized by analytical and spectroscopic methods.

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Comparison of different heterocyclic scaffolds as substrate analog PDE5 inhibitors

Cited by 42 publications

References 21 publications

Phosphodiesterase 5 Inhibitors - Drug Design and Differentiation Based on Selectivity, Pharmacokinetic and Efficacy Profiles

Phosphodiesterase 5 Inhibitors - Drug Design and Differentiation Based on Selectivity, Pharmacokinetic and Efficacy Profiles

Novel Pieces for the Emerging Picture of Sulfoximines in Drug Discovery: Synthesis and Evaluation of Sulfoximine Analogues of Marketed Drugs and Advanced Clinical Candidates

A Convenient Synthesis of New Pyrazolo[4,3‐d]pyrimidines and Their Fused Heterocycles

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