Structure–activity studies for a novel series of tricyclic dihydropyridopyrazolones and dihydropyridoisoxazolones as KATP channel openers

Drizin, Irene; Altenbach, Robert J.; Buckner, Steven A.; Whiteaker, Kristi L.; Scott, Victoria E.; Darbyshire, John F.; Jayanti, Venkata; Henry, Rodger F.; Coghlan, Michael J.; Gopalakrishnan, Murali; Carroll, William A.

doi:10.1016/j.bmc.2004.01.038

Cited by 37 publications

(8 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Incorporating a methyl group adjacent to the dihydropyridine nitrogen significantly increases both activity and metabolic stability. In vitro tests on the tissue from pig bladder strips provide further confirmation of the K ATP activity of these compounds [93].…”

Section: Effects Of Kcos On Organsmentioning

confidence: 97%

ATP-Sensitive Potassium Channel Openers and 2,3-Dimethyl-2-Butylamine Derivatives

Wang¹,

Tang²,

Wang³

et al. 2007

CMC

View full text Add to dashboard Cite

ATP-sensitive potassium (K(ATP)) channels have important functions through their coupling of cellular energetic networks and their ability to decode metabolic signals, and they are implicated in diseases of many organs. K(ATP) channels are formed by the physical association between the inwardly rectifier potassium channels (Kir6.x) and the regulatory sulfonylurea receptor subunit (SUR), which form a hetero-octameric complex. Different subtypes of K(ATP) channels exist in various tissues. K(ATP) channel openers (KCOs) are classified into nine chemical families according to their molecular structures: (1) benzopyrans, (2) cyanoguanidines, (3) thioformamides, (4) pyrimidine derivatives, (5) pyridine derivatives, (6) benzothiadiazines, (7) dihydropyridines, (8) nicotinamide derivatives, and (9) aliphatic amines. Although the model also predicts that KCOs have four co-binding areas, it was hypothesized that the main contribution lies in the binding domain of hydrophobicity of the side chain. A series of compounds containing the skeleton of the aliphatic secondary amines as a side chain was designed. It was found that N-isopropyl 2,3-dimethyl-2-butylamine (iptakalim, 91) is a novel KCOs. Iptakalim regulates the pore selectively of the inwardly rectifier potassium channel and dilates smaller arteries, but has little effect on vasodilatation of the aorta. Iptakalim administered p.o. has selective and long-lasting antihypertensive effects in hypertensive animals and does not induce tolerance, but has little effect on blood pressure in normotensive animals. Meanwhile, it also reverses cardiovascular remodeling and protects the brain and kidney against damage caused by hypertension in animal models. Iptakalim is in phase II clinical trials now and has a promising future as a treatment for hypertension.

show abstract

Section: Effects Of Kcos On Organsmentioning

confidence: 97%

ATP-Sensitive Potassium Channel Openers and 2,3-Dimethyl-2-Butylamine Derivatives

Wang¹,

Tang²,

Wang³

et al. 2007

CMC

View full text Add to dashboard Cite

show abstract

“…In addition to the activities mentioned above, pyrazolones have been shown to inhibit the proteins including K ATP channel protein, phosphodiesterase (PDE), aromatase, divalent metal transporter 1 (DMT1), human carboxylesterase1 (hCE1) and transforming growth factor (TGF) bR1, indicating the multiple targets therapeutic action and favorable drug-likeness of pyrazolone derivatives. Drizin and co-workers [133] designed and synthesized a cluster of pyrazolone derivatives as K ATP channel openers inspired from disclosed compounds (the skeleton of 177 and 178, Fig. 19), together with the investigation of SAR.…”

Section: Protein Inhibitorsmentioning

confidence: 99%

Pyrazolone structural motif in medicinal chemistry: Retrospect and prospect

Zhao

Dai

et al. 2020

European Journal of Medicinal Chemistry

150

View full text Add to dashboard Cite

a b s t r a c tThe pyrazolone structural motif is a critical element of drugs aimed at different biological end-points. Medicinal chemistry researches have synthesized drug-like pyrazolone candidates with several medicinal features including antimicrobial, antitumor, CNS (central nervous system) effect, anti-inflammatory activities and so on. Meanwhile, SAR (Structure-Activity Relationship) investigations have drawn attentions among medicinal chemists, along with a plenty of analogues have been derived for multiple targets. In this review, we comprehensively summarize the biological activity and SAR for pyrazolone analogues, wishing to give an overall retrospect and prospect on the pyrazolone derivatives.

show abstract

“…In [8] the relation between the structure of thiopyran-3-one 1,1-dioxides and their ability to act as agonists of these channels was analyzed. One of the most powerful modulators of ATP-dependent potassium channels is compound A-27863, which is at present undergoing preclinical trials [9][10][11][12]. The above-mentioned types of activity have been confirmed in vitro for a series of A-278637 analogs [13].…”

Section: Biological Activity Of β-Keto Sulfonesmentioning

confidence: 92%

“…The obtained compounds 117 can act as modulators of ATP-dependent potassium channels. ( ) n + A similar method for the production of dihydropyridines but with ammonia and a twofold excess of the keto sulfone was described in [9][10][11][12][13].…”

mentioning

confidence: 99%