Development of tetrazole bioisosteres in angiotensin II antagonists

Ferrari, Bernard; Taillades, J.; Perreaut, P.; Bernhart, C.; Gougat, J.; Guiraudou, P.; Cazaubon, Catherine; Roccon, Alain; Nisato, Dino; Fur, G. Le; Brelière, Jean-Claude

doi:10.1016/s0960-894x(01)81120-3

Cited by 12 publications

(4 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Unexpectedly, a number of the sulfonamides showed very significant binding in the AT2 receptor assay (e.g., AT2 IC50 17 nM for 92). Preferred sulfonamide substituents for AT2 potency enhancement included ohalobenzoyl (16,18,23,24), suitably substituted heteroaroyl (37,39,41,51,53,59), and l,3-dithiolan-2ylcarbonyl (87), as well as certain compact, branched groups like iert-butylacetyl (64) and tert-butoxycarbonyl (92). In such compounds, the iV-acyl or N-alkoxycarbonyl substituent on the sulfonamide may contribute substantial binding energy by direct interaction with a hydrophobic region of the AT2 receptor.…”

Section: Discussionmentioning

confidence: 99%

“…Chloro substitution at the metaor para-positions (20,21) gave less effective compounds. However, both the 2,3-dichloro ( 22) and 2,5-dichloro (23) derivatives had subnanomolar ATi potency. As in the case of the halogens, trifluoromethyl was very effective at the 2-position of the benzoyl (25) but was detrimental at the 3-position ( 26) and 4-position (27).…”

mentioning

confidence: 98%

“…Although AT2 structure-activity relationships sometimes paralleled those at ATi, at other times there was considerable divergence between the two receptor subtypes. For example, the 2,3dichlorobenzoyl (22) and 2,5-dichlorobenzoyl (23) derivatives had similar ATi affinity, but the 2,5-dichloro compound was 30-fold more effective as an AT2 antagonist. In the case of 19, the 4,4,4-trifluorobutyl modification at C5 of the heterocycle was very detrimental to AT2 potency (cf.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Triazolinone Biphenylsulfonamide Derivatives as Orally Active Angiotensin II Antagonists with Potent AT1 Receptor Affinity and Enhanced AT2 Affinity

Ashton¹,

Chang²,

Flanagan³

et al. 1994

J. Med. Chem.

View full text Add to dashboard Cite

Several series of 2,4-dihydro-2,4,5-trisubstituted-3H-1,2,4-triazol-3-ones with acidic sulfonamide replacements of tetrazole at the 2'-position of the biphenyl-4-ylmethyl side chain at N4 were prepared and tested as angiotensin II (AII) antagonists. Preferred substituents on the triazolinone ring were n-butyl at C5 and 2-(trifluoromethyl)phenyl at N2. Subnanomolar IC50 values at the AT1 receptor subtype were observed for a variety of acylsulfonamides, including aroyl, heteroaroyl, and cycloalkylcarbonyl derivatives. Certain other acidic sulfonamides, such as sulfonylcarbamates and disulfimides also displayed high affinity for the AT1 receptor. In addition, AT2 binding for some of these compounds was increased by as much as 1000-fold over the corresponding tetrazole (e.g., AT2 IC50 17 nM for the tert-butyl sulfonylcarbamate 92). When evaluated for inhibition of the AII pressor response, the benchmark benzoylsulfonamide 9 (L-159,913) was efficacious in several species and was superior to losartan (1a) in conscious rhesus monkeys. Several subsequent analogues, including the 2-chlorobenzoyl (18), (3-chlorothiophene-2-yl)carbonyl (51), ((S)-2,2-dimethylcyclopropyl)carbonyl (80), and tert-butoxycarbonyl (92) derivatives, were highly effective in rats, surpassing 9 and losartan in duration of action and/or potency. Compound 18 (L-162,223) displayed very prolonged AII antagonism in the rat model (> 24 h at 1 mg/kg iv). At 1 mg/kg po in rats, 18 and 92 (L-162,234) produced 85-87% peak inhibition of the AII pressor response with duration exceeding 6 h. The identification of triazolinone-based sulfonamide derivatives combining high AT1 affinity, considerably enhanced AT2 potency, and favorable in vivo properties provides insights relevant to the design of dual AT1/AT2 receptor antagonists.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 98%

mentioning

confidence: 99%

See 1 more Smart Citation

Triazolinone Biphenylsulfonamide Derivatives as Orally Active Angiotensin II Antagonists with Potent AT1 Receptor Affinity and Enhanced AT2 Affinity

Ashton¹,

Chang²,

Flanagan³

et al. 1994

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

“…In addition to the acidic heterocycles already mentioned, there are others that have emanated from Merck (compounds 22, 23, 25, 26) (Kim et al, 1994), Sanofi (compounds 27, 28, 32-37) (Ferrari et al, 1994), Wyeth-Ayerst (compounds 38, 39) (Soll et al, 1993), and Takeda (compounds 24, 29-31) (Kohara et al, 1996). The heterocycles that give rise to stronger binding affinities have their negative charge localized at a distance greater than 2.3 Å as per the above discussion.…”

Section: The Search For Tetrazole Replacementsmentioning

confidence: 99%