Triazolinones as nonpeptide angiotensin II antagonists. 2. discovery of a potent and orally active triazolinone acylsulfonamide

Chang, Linda; Ashton, Wallace T.; Flanagan, Kelly L.; Naylor, Elizabeth M.; Chakravarty, Prasun K.; Patchett, Arthur A.; Greenlee, William J.; Bendesky, Robert J.; Chen, T.-B.; Faust, Kristie A.; Kling, Paul J.; Schaffer, L. W.; Schorn, Terry W.; Zingaro, Gloria J.; Chang, Raymond S.L.; Lotti, Victor J.; Kivlighn, Salah D.; Siegl, P. K. S.

doi:10.1016/s0960-894x(01)81132-x

Cited by 13 publications

(9 citation statements)

References 10 publications

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“…With respect to binding to the ATi receptor, in the R1 = n-butyl series, ATi IC50 values were only slightly affected by changes in R2 (e.g., 3b, 5b, and 25), R3 (e.g., 5b and 8-13), or R4 (e.g., 3b and [17][18][19][20][21][22][23]. This is also true for compounds studied in the R1 = n-propyl series (28)(29)(30)(31)(32)(33)(34)(35)(36).…”

Section: Biological Results and Discussionmentioning

confidence: 99%

Potent and orally active angiotensin II receptor antagonists with equal affinity for human AT1 and AT2 subtypes

Chang¹,

Ashton²,

Flanagan³

et al. 1995

J. Med. Chem.

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In order to block the effects induced by the interactions between angiotensin II (AII) and both AT1 and AT2 receptors, we have pursued the discovery of orally active non-peptide AII antagonists that exhibit potent and equal affinity for human AT1 and AT2 receptor subtypes. A series of previously prepared nanomolar (IC50) trisubstituted 1,2,4-triazolinone biphenyl-sulfonamide dual-acting AII antagonists has been modified at five different positions in order to increase AT2 binding affinity, maintain AT1 activity, and reduce the human adrenal AT2/AT1 potency ratio (IC50 ratio) from > or = 10. The targeted human adrenal potency ratio of < or = 1 was achieved with a number of compounds possessing an ethyl group at C5 of the triazolinone and a 3-fluoro substituent at the N4-biarylmethyl moiety. The most favored of these was compound 44 which exhibited subnanomolar potency at both the AT1 (rabbit aorta) and AT2 (rat midbrain) receptors, with a slight preference for the latter, and had a human adrenal AT2/AT1 IC50 ratio of 1. This tert-butyl sulfonylcarbamate with an N2-[2-bromo-5-(valerylamino)phenyl] substituent had excellent iv activity at 1 mg/kg (100% peak inhibition, > or = 4 h duration of action) and is orally active at 3 mg/kg with > 6 h duration of action in a conscious rat model. The present study shows that the NH of the amide on the N2-aryl moiety is not required for subnanomolar binding affinity to either receptor subtype, although a keto functionality at this position is essential for acceptable AT2 binding. Receptor-ligand binding interactions derived from the structure-activity relationships are discussed with respect to both receptor subtypes.

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Section: Biological Results and Discussionmentioning

confidence: 99%

Potent and orally active angiotensin II receptor antagonists with equal affinity for human AT1 and AT2 subtypes

Chang¹,

Ashton²,

Flanagan³

et al. 1995

J. Med. Chem.

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“…This antagonist showed blockade of Ang II pressor response in conscious rats for >6 h after oral administration (3 mg/kg) . Although there was no direct pharmacological readout of an AT 2 effect in vivo , radioligand assays of plasma samples withdrawn from rats dosed with L-159,689 indicated that equivalence of AT 1 and AT 2 binding was maintained for >8 h. Although L-159,689 showed an excellent in vivo profile in rats, no oral activity was demonstrated in dogs, possibly due to rapid in vivo glucuronidation of the tetrazole moiety in this species …”

Section: Balanced Angiotensin II Antagonistsmentioning

confidence: 98%

Nonpeptide Angiotensin II Receptor Antagonists: The Next Generation in Antihypertensive Therapy

et al. 1996

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“…Having validated that the scaffold replacement procedure operated as expected in test cases, an AUTOSTERE run was conducted across the entire 10 426 nonredundant ligand–protein set using a triazolinone as the screening (replacement) scaffold. This scaffold was selected because it has been observed in marketed compounds, , such as posoconazole, an antifungal, and other compounds in preclinical or clinical development including selective 5HT 1A agonists developed within our group (Figure ).…”

Section: Resultsmentioning

confidence: 99%

“…Having validated that the scaffold replacement procedure operated as expected in test cases, an AUTOSTERE run was conducted across the entire 10 426 nonredundant ligand−protein set using a triazolinone as the screening (replacement) scaffold. This scaffold was selected because it has been observed in marketed compounds, 14,15 such as posoconazole, an antifungal, and other compounds in preclinical or clinical development 16 including selective 5HT 1A agonists developed within our group (Figure 3). Not only is the scaffold observed in multiple IND candidates, but also it has interesting structural properties in its ability to potentially replace a variety of noncyclic motifs containing H-bond acceptors, such as amides or ureas, potentially increasing rigidity in these and similar polar substructures.…”

Section: ■ Methodsmentioning

confidence: 99%

AUTOSTERE: Systematic Search for Scaffold Replacement Opportunities within Structural Databases

Heal¹,

Sheridan²,

Kulkarni³

et al. 2021

J. Chem. Inf. Model.

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Medicinal chemists often bias toward working with scaffolds with which previously they have had direct experience and successes. In this way, it is often the case that scaffolds which have proven tractable within a research group are "reused" across multiple and sometimes unrelated drug targets. With this concept in mind, we designed a new computer algorithm AUTOSTERE which could systematically assess the opportunities to replace any part of any molecule within an entire database of known ligand structures with a target scaffold and automatically evaluate the potential designs in the context of the original ligand's protein environment. As such, it performs scaffold replacement on an unprecedented scale and suggests new target opportunities for preferred chemistries rather than the conventional reverse situation. The results of this approach for one scaffold, a substituted triazolinone, applied to a set of 10 426 ligand conformations extracted from the PDB are described. This led to the identification of ∼600 novel ligands incorporating the triazolinone scaffolds in complex with their predicted drug targets. From these, design examples are provided for HSP-90, cathepsin K, and TIE-2 kinase. A further study involved the searching for possible drug targets for unusual pyridopyrimidine cores. This process resulted in the identification of potential novel HIV reverse transcriptase inhibitors which were synthesized and shown to exhibit similar in vitro potencies to marketed compounds. Overall, the methodology described provides a powerful new approach to identify new target opportunities for scaffolds of provenance.

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Triazolinones as nonpeptide angiotensin II antagonists. 2. discovery of a potent and orally active triazolinone acylsulfonamide

Cited by 13 publications

References 10 publications

Potent and orally active angiotensin II receptor antagonists with equal affinity for human AT1 and AT2 subtypes

Potent and orally active angiotensin II receptor antagonists with equal affinity for human AT1 and AT2 subtypes

Nonpeptide Angiotensin II Receptor Antagonists: The Next Generation in Antihypertensive Therapy

AUTOSTERE: Systematic Search for Scaffold Replacement Opportunities within Structural Databases

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