Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

At each of several stabilized temperatures between 7.0 and 43.8 degrees C, increases in dog-kidney, Na(+)-, K(+)-ATPase catalytic activity were usually observed in association with exposure for 5 min to 9.14 GHz CW microwave radiation in a thin tubular reactor. However, at 24.9 degrees C, a 23% decrease occurred. Comparisons of activity of ouabain-inhibited reactions revealed that the efficacy of the cardiac glycoside as an inhibitor of ATPase activity was severely diminished by the microwave field. The ouabain-site control mechanism may be a specific microwave target at this exposure frequency. Experimental results can be interpreted in terms of molecular structural changes or direct energy input. The estimated SAR of energy that was incident on preparations is 20 W/kg.
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PMID:Ouabain inhibition of kidney ATPase is altered by 9.14 GHz radiation. 164 5

Quinazolines bearing a secondary 4-(arylamino) substituent demonstrate an SAR for inhibition of the gastric (H+/K+)-ATPase different from the previously described 3-acylquinolines, suggesting that, although these compounds are also K(+)-competitive, they probably bind to the enzyme in a different orientation. Compounds bearing a tertiary 4-(arylamino) substituent, however, in particular 4-(N-methylarylamino), appear to possess an SAR quite similar to the 3-acylquinolines. We show that this arises from the effect of the N-methylation, which is to orientate the 4-(arylamino) substituent syn to C5, analogous to the 3-acylquinolines. Compounds possessing both a 4-(N-methylarylamino) substituent and a 2-(arylamino) substituent proved to be very potent, K(+)-competitive inhibitors of K(+)-stimulated ATPase activity with Ki values down to 12 nM. Some compounds also proved to be effective inhibitors of stimulated acid secretion in both the rat and dog when dosed intravenously. However, although a number of these demonstrated activity after oral administration in the dog, the level and variability precluded further evaluation.
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PMID:Reversible inhibitors of the gastric (H+/K+)-ATPase. 5. Substituted 2,4-diaminoquinazolines and thienopyrimidines. 762 14

The proton pump expressed on the plasma membrane of bone resorbing osteoclasts, and which mediates the acidification of the extracellular environment in resorption lacuna, belongs to the family of vacuolar H(+)-ATPases, which are enzymes ubiquitously distributed among all cells and are evolutionary conserved. These pumps have two functional domains: a peripherally associated cytoplasmatic section, and a proton channel composed of several subunits one of which, the 116 kDa subunit, is expressed exclusively in osteoclasts and confers unique functional and pharmacological properties to the osteoclast V-ATPase. It was demonstrated that inhibition of this pump can abolish bone resorption; therefore, osteoclast-selective inhibitors could provide novel and useful agents for the treatment of osteoporosis. This paper reviews the medicinal chemistry approaches that have allowed to obtain such new agents, most of which have been designed starting from the natural macrolide antibiotic bafilomycin A(1), a potent and selective inhibitor of all V-ATPases. Identification of SAR and of minimal structural requirements for bafilomycin activity have allowed to obtain (2Z,4E)-5-(5,6-dichloroindolyl)-2-methoxy-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pentadienamide (SB-242784) which inhibits the osteoclastic proton pump and bone resorption in vitro. Although it inhibits the activity of non-osteoclastic proton pumps as well, it appears to have reasonable selectivity and its administration for 6 months prevented the loss of femoral and vertebral BMD in ovariectomized rats, without any significant renal effects in control and acid-loaded animals. Other independent approaches that did not start from bafilomycin have led to the discovery of a different class of V-ATPase inhibitors, among which 4-(2,6-dichlorobenzoyl)amino-2-trifluoromethyl(benzoimidazol-1-yl)acetyl morpholine (FR177995) was the most effective in preventing bone resorption in an ovariectomized rat model of osteoporosis. These compounds are of great pharmaceutical and medical interest because they allow to target a specific function of the osteoclast; however, only clinical trials might demonstrate whether they have significant advantages over other inhibitors of bone resorption for the treatment of osteoporosis.
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PMID:Selective inhibition of osteoclast vacuolar H(+)-ATPase. 1217 17

Multidrug resistance is brought about largely by membrane transport proteins such as P-glycoprotein (P-gp). We have developed a quantitative structure-activity relationship (QSAR) for P-gp-associated ATPase activity for a diverse set of 22 drugs, and found that such activity is related to substrate molecular size and polarity. We have also developed a QSAR for drug efflux from the blood-brain barrier of another diverse set of 22 drugs, and found that such efflux is a function of drug size and polarisability. Thirdly, we have carried out a QSAR analysis of the ability of 157 phenothiazines and related drugs to reverse multidrug resistance. We were unable to obtain a good QSAR for the whole data-set, but when we divided the data-set into sub-sets of closely related structures, a series of good correlations was obtained, most of which incorporated descriptors that model molecular size and polarity/polarisability. In no instance did we find any evidence that hydrogen bonding or hydrophobicity play a part in multidrug resistance or its reversal, despite that fact that several other workers have reported that these effects appear to be important here.
SAR QSAR Environ Res
PMID:QSAR studies on P-glycoprotein-regulated multidrug resistance and on its reversal by phenothiazines. 1475 87

Synthesis and SAR of substituted pyrrolotriazine-4-one analogues as Eg5 inhibitors are described. Many of these analogues displayed potent inhibitory activities in the Eg5 ATPase and A2780 cell proliferation assays. In addition, pyrrolotriazine-4-one analogue 26 demonstrated in vivo efficacy in an iv P388 murine leukemia model. Both NMR and X-ray crystallographic studies revealed that these analogues bind to an allosteric site on the Eg5 protein.
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PMID:Synthesis and SAR of pyrrolotriazine-4-one based Eg5 inhibitors. 1673 Sep 79

This review explains why the chaperone Hsp90 is an exciting protein target for the discovery of new drugs to treat cancer in the clinic, and summarises the properties of natural product derived inhibitors before relating the discovery and current state of development of synthetic pyrazole compounds. Blockade of Hsp90 results in reduced cellular levels of several proteins implicated in cancer including CDK4, ERBB2 and C-RAF, and causes simultaneous inhibition of cancer cell proliferation in culture and of tumor xenograft growth in vivo. Hsp90 has an ATPase domain that is necessary for its Hsp chaperone function, and X-ray crystallography has shown that natural product inhibitors (geldanamycin, radicicol) of Hsp90 function bind to this domain. High throughput assays focusing on the ATPase activity of Hsp90 were developed and used to discover novel chemical starting points for cancer drug discovery. The discovery, synthesis and SAR of 3,4-diaryl pyrazoles is described. X-Ray crystallography of protein-inhibitor complexes revealed important interactions involving the resorcinol substituent at C-3, and these X-ray structures strongly influenced subsequent medicinal chemistry research that has resulted in highly potent inhibitors with sub-micromolar activity in cells. SAR and X-ray data are summarised for analogues in which the 4-phenyl substituent is replaced by amides or piperazine derivatives. Prospects for the pyrazoles as they progress towards clinical development are discussed in relation to current Phase I trials with derivatives of geldanamycin.
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PMID:Discovery and development of pyrazole-scaffold Hsp90 inhibitors. 1684 56

A modular total synthesis of the potent V-ATPase inhibitors archazolid A and B is reported. The convergent preparation was accomplished by late-stage diversification of joint intermediates. Key synthetic steps involve asymmetric boron-mediated aldol reactions, two consecutive Still-Gennari olefinations to set the characteristic (Z,Z)-diene system, a Brown crotyboration, and a diastereoselective aldol condensation of highly elaborate intermediates. For macrocyclization, both an HWE reaction and a Heck coupling were successfully employed to close the 24-membered macrolactone. During the synthetic campaign, a generally useful protocol for an E-selective Heck reaction of nonactivated alkenes and a method for the direct nucleophilic displacement of the Abiko-Masamune auxiliary with sterically hindered nucleophiles were developed. The expedient and flexible strategy will enable further SAR studies of the archazolids and more detailed evaluations of target-inhibitor interactions.
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PMID:Modular total synthesis of archazolid A and B. 1973 63

Heat shock protein 90 (Hsp90) is an ATP-dependent chaperone which is involved in the post-translational maturation and stabilization of over one hundred proteins ("its clients"). In the absence of Hsp90's chaperoning, its clients are misfolded and degraded via ubiquitin-proteasome pathway. It has become the focus of intense drug discovery efforts as its activity has been implicated in diverse pathologies ranging from oncology to neurodegenerative and infectious diseases. The most promising inhibitors reported to date inhibit the ATPase activity by binding to the N-terminal ATP pocket. Radicicol, a member of the resorcylic acid lactones (RALs), represents an important pharmacophore to this end. Efforts towards the development of this pharmacophore and its SAR are reviewed herein.
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PMID:Hsp90 inhibition with resorcyclic acid lactones (RALs). 1986 Jul 33

We report the identification of a novel biaryl template for H(+)/K(+) ATPase inhibition. Evaluation of critical SAR features within the biaryl imidazole framework and the use of pharmacophore modelling against known imidazopyridine and azaindole templates suggested that the geometry of the molecule is key to achieving activity. Herein we present our work optimising the potency of the molecule through modifications and substitutions to each of the ring systems. In particular sub-micromolar potency is achieved with (4b) presumably through a proposed intramolecular hydrogen bond that ensures the required imidazole basic centre is appropriately located.
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PMID:Discovery of biaryl inhibitors of H+/K+ ATPase. 2005 60

Valosin-containing protein (VCP; also known as p97) is a member of the AAA ATPase family with a central role in the ubiquitin-degradation of misfolded proteins. VCP also exhibits antiapoptotic function and metastasis via activation of nuclear factor kappa-B signaling pathway. We have discovered that 2-anilino-4-aryl-1,3-thiazoles are potent drug-like inhibitors of this enzyme. The identified compounds show low nanomolar VCP potency, demonstrate SAR trends, and show activity in a mechanism based cellular assay. This series of compounds represents the first steps towards a novel, small molecule VCP inhibitor as a cancer therapeutic.
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PMID:2-Anilino-4-aryl-1,3-thiazole inhibitors of valosin-containing protein (VCP or p97). 2013 40


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