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Nephrolithiasis: etiology, stone composition, medical management, and prevention
Published in J Kellogg Parsons, E James Wright, The Brady Urology Manual, 2019
Acetohydroxamic acid: Inhibits urease20–70% severe side effects.
Methenamine Mandelate and Methenamine Hippurate
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Matthew A. Murphy, M. Lindsay Grayson
Because the antibacterial activity produced by these compounds in the urine is due to liberated formaldehyde (to which all microorganisms are susceptible), both methenamine mandelate and methenamine hippurate demonstrate activity against almost all common Gram-positive and Gram-negative bacteria, and also against some fungi. UTIs due to urea-splitting organisms, such as Proteus species, are far less likely to respond to these agents; the urine cannot be sufficiently acidified in the presence of these infections, and therefore formaldehyde is not liberated. The use of acetohydroxamic acid, a urease inhibitor, together with methenamine, has been suggested for the treatment of urinary infections caused by Proteus species (Musher et al., 1976), but the clinical relevance of this is uncertain.
The Scientific Basis of Urinary Stone Formation
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
Treatment of infected stone patients usually involves the combined efforts of the surgeon and the physician. The first important stage is to remove the stone completely and, if possible, to correct any anatomical obstruction that might have caused the underlying infection. Medical management is necessary before and after stone removal to sterilize the urine (94). This may not always be easy to achieve since the infecting organism may be resistant to several antibiotics (95,96). In this situation, urease-inhibiting drugs, such as acetohydroxamic acid or one of its analogues, may be helpful (97–99), although there may be side-effects (Fig. 18) (97). A high fluid intake is necessary in all patients, and some acidification may be required to lower the urine pH to around 6. Drinking cranberry juice may be beneficial in this respect (100). It should be noted that cranberry juice is the only fruit juice known to acidify urine; all other fruit juices including those which are acidic to the taste, alkalinise urine.
Thermodynamic profiling for fragment-based lead discovery and optimization
Published in Expert Opinion on Drug Discovery, 2020
György G. Ferenczy, György M. Keserű
One of the first studies on the impact of binding thermodynamics on fragment optimization has been published by Bertini et al. [93]. The authors investigated the optimization of low affinity fragments to nanomolar MMP12 inhibitors by evaluating the key compounds along the optimization path by biochemical and ITC measurements, and X-ray crystallography. Matrix metalloproteinases are zinc containing proteases. Most of the high affinity MMP inhibitors form direct interactions with the zinc ion located at the substrate binding groove. Due to the chelating properties of hydroxamic acids, the identification of the low affinity and nonspecific acetohydroxamic acid (1) was not unexpected. In fact, 1 binds to MMP12 with a Kd of 6.18 mM, its binding mode has been confirmed by X-ray crystallography and the subsequent ITC analysis revealed this fragment as a high enthalpy binder. The first optimization step was realized by a linking strategy connecting the acetyl group of 1 to the terminal amino group of the 4-methoxy-benzenesulfonamide (2) that binds to the S1’ pocket of MMP12 (Figure 2). This modification resulted in a dramatic improvement in the potency that was increased by five orders of magnitude, reaching the Kd of 61 nM. Analyzing the thermodynamic profiles of the linked fragments, the observed improvement in Kd can be traced back to the much improved binding entropy of 3.
A patent update on therapeutic applications of urease inhibitors (2012–2018)
Published in Expert Opinion on Therapeutic Patents, 2019
Abdul Hameed, Mariya Al-Rashida, Maliha Uroos, Syeda Uroos Qazi, Sadia Naz, Marium Ishtiaq, Khalid Mohammed Khan
In conclusion, urease is an important drug target for the treatment of various bacterial infections. In markets, there is a lack of new urease inhibitor drugs. The acetohydroxamic acid (Lithostat) remains the only available urease inhibitor drug in the market. However, Lithostat is known to have many adverse effects as well. Hence, there is a need to discover new molecules that are potent inhibitors of urease enzyme and also possess an acceptable/safe toxicological profile. Herein, we have reviewed small molecules patented as urease inhibitors from 2012 to 2018. These include thiazole containing Schiff bases, a wide variety of azaheterocyclic compounds, and thiophosphoryl triamide derivatives. All these compounds are highly potent inhibitors of urease. Keeping in mind that drug repurposing can significantly reduce the cost of drug development, some existing drugs, ropinirole and captopril, were evaluated as urease inhibitors with much promising results; consequently, this novel application of existing/already available drugs as potential treatment for urease-related bacterial infections was patented. This expands the searchable chemical space available and gives hope of being able to find similar existing drugs that may have potent urease inhibitory activity.
N-monoarylacetothioureas as potent urease inhibitors: synthesis, SAR, and biological evaluation
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Wei-Yi Li, Wei-Wei Ni, Ya-Xi Ye, Hai-Lian Fang, Xing-Ming Pan, Jie-Ling He, Tian-Li Zhou, Juan Yi, Shan-Shan Liu, Mi Zhou, Zhu-Ping Xiao, Hai-Liang Zhu
In the past decades, thousands of urease inhibitors have been reported, and they were designed exclusively by either attacking the metallocenter or mimicking the substrate of ureases7–10. However, urease has a highly specific substrate urea, which makes it very challenging for the development of urease inhibitors. In spite of enormous efforts being made, only acetohydroxamic acid (AHA) has so far been approved by FDA for the treatment of urinary tract infections. Novel urease inhibitors with high potency are urgently needed. We therefore have focussed our efforts on this field for several years, and some potent urease inhibitors with structural diversity were reported such as catechols, diarylethylenes, flavonoids, arylamides, and hydroxamic acids11–15.