Abstract
Out of the prominent global ailments, tuberculosis (TB) is still one of the leading causes of death worldwide due to infectious disease. Development of new drugs that shorten the current tuberculosis treatment time and have activity against drug resistant strains is of utmost importance. Towards these goals we have focused our efforts on developing novel anti-TB compounds with the general structure of 1-adamantyl-3-phenyl urea. This series is active against Mycobacteria and previous lead compounds were found to inhibit the membrane transporter MmpL3, the protein responsible for mycolic acid transport across the plasma membrane. However, these compounds suffered from poor in vitro pharmacokinetic (PK) profiles and they have a similar structure/SAR to inhibitors of human soluble epoxide hydrolase (sEH) enzymes. Therefore, in this study the further optimization of this compound class was driven by three factors: (1) to increase selectivity for anti-TB activity over human sEH activity, (2) to optimize PK profiles including solubility and (3) to maintain target inhibition. A new series of 1-adamantyl-3-heteroaryl ureas was designed and synthesized replacing the phenyl substituent of the original series with pyridines, pyrimidines, triazines, oxazoles, isoxazoles, oxadiazoles and pyrazoles. This study produced lead isoxazole, oxadiazole and pyrazole substituted adamantyl ureas with improved in vitro PK profiles, increased selectivity and good anti-TB potencies with sub μg/mL minimum inhibitory concentrations.
| Original language | English |
|---|---|
| Pages (from-to) | 2587-2599 |
| Number of pages | 13 |
| Journal | Bioorganic and Medicinal Chemistry |
| Volume | 21 |
| Issue number | 9 |
| DOIs | |
| State | Published - May 1 2013 |
| Externally published | Yes |
Fingerprint
All Science Journal Classification (ASJC) codes
- Pharmaceutical Science
- Drug Discovery
- Organic Chemistry
- Molecular Medicine
- Molecular Biology
- Clinical Biochemistry
- Biochemistry
Cite this
Design, synthesis and anti-tuberculosis activity of 1-adamantyl-3- heteroaryl ureas with improved in vitro pharmacokinetic properties. / North, E. Jeffrey; Scherman, Michael S.; Bruhn, David F.; Scarborough, Jerrod S.; Maddox, Marcus M.; Jones, Victoria; Grzegorzewicz, Anna; Yang, Lei; Hess, Tamara; Morisseau, Christophe; Jackson, Mary; McNeil, Michael R.; Lee, Richard E.
In: Bioorganic and Medicinal Chemistry, Vol. 21, No. 9, 01.05.2013, p. 2587-2599.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Design, synthesis and anti-tuberculosis activity of 1-adamantyl-3- heteroaryl ureas with improved in vitro pharmacokinetic properties
AU - North, E. Jeffrey
AU - Scherman, Michael S.
AU - Bruhn, David F.
AU - Scarborough, Jerrod S.
AU - Maddox, Marcus M.
AU - Jones, Victoria
AU - Grzegorzewicz, Anna
AU - Yang, Lei
AU - Hess, Tamara
AU - Morisseau, Christophe
AU - Jackson, Mary
AU - McNeil, Michael R.
AU - Lee, Richard E.
PY - 2013/5/1
Y1 - 2013/5/1
N2 - Out of the prominent global ailments, tuberculosis (TB) is still one of the leading causes of death worldwide due to infectious disease. Development of new drugs that shorten the current tuberculosis treatment time and have activity against drug resistant strains is of utmost importance. Towards these goals we have focused our efforts on developing novel anti-TB compounds with the general structure of 1-adamantyl-3-phenyl urea. This series is active against Mycobacteria and previous lead compounds were found to inhibit the membrane transporter MmpL3, the protein responsible for mycolic acid transport across the plasma membrane. However, these compounds suffered from poor in vitro pharmacokinetic (PK) profiles and they have a similar structure/SAR to inhibitors of human soluble epoxide hydrolase (sEH) enzymes. Therefore, in this study the further optimization of this compound class was driven by three factors: (1) to increase selectivity for anti-TB activity over human sEH activity, (2) to optimize PK profiles including solubility and (3) to maintain target inhibition. A new series of 1-adamantyl-3-heteroaryl ureas was designed and synthesized replacing the phenyl substituent of the original series with pyridines, pyrimidines, triazines, oxazoles, isoxazoles, oxadiazoles and pyrazoles. This study produced lead isoxazole, oxadiazole and pyrazole substituted adamantyl ureas with improved in vitro PK profiles, increased selectivity and good anti-TB potencies with sub μg/mL minimum inhibitory concentrations.
AB - Out of the prominent global ailments, tuberculosis (TB) is still one of the leading causes of death worldwide due to infectious disease. Development of new drugs that shorten the current tuberculosis treatment time and have activity against drug resistant strains is of utmost importance. Towards these goals we have focused our efforts on developing novel anti-TB compounds with the general structure of 1-adamantyl-3-phenyl urea. This series is active against Mycobacteria and previous lead compounds were found to inhibit the membrane transporter MmpL3, the protein responsible for mycolic acid transport across the plasma membrane. However, these compounds suffered from poor in vitro pharmacokinetic (PK) profiles and they have a similar structure/SAR to inhibitors of human soluble epoxide hydrolase (sEH) enzymes. Therefore, in this study the further optimization of this compound class was driven by three factors: (1) to increase selectivity for anti-TB activity over human sEH activity, (2) to optimize PK profiles including solubility and (3) to maintain target inhibition. A new series of 1-adamantyl-3-heteroaryl ureas was designed and synthesized replacing the phenyl substituent of the original series with pyridines, pyrimidines, triazines, oxazoles, isoxazoles, oxadiazoles and pyrazoles. This study produced lead isoxazole, oxadiazole and pyrazole substituted adamantyl ureas with improved in vitro PK profiles, increased selectivity and good anti-TB potencies with sub μg/mL minimum inhibitory concentrations.
UR - http://www.scopus.com/inward/record.url?scp=84876129597&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84876129597&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2013.02.028
DO - 10.1016/j.bmc.2013.02.028
M3 - Article
C2 - 23498915
AN - SCOPUS:84876129597
VL - 21
SP - 2587
EP - 2599
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 9
ER -