A new class of balanced AT1/AT2 angiotensin II antagonists: quinazolinone AII antagonists with acylsulfonamide and sulfonylcarbamate acidic functionalities
The development of a series of potent quinazilinone derived angiotensin II antagonists capable of inhibition of AII binding to both AT1 and AT2 receptor subtypes is described. L-162,393 (R1=CON(Me)i-Pr, R2=H, R3=Bu, R4=CO2CH2CH2CHMe2) was shown to inhibit the the AII induced pressor response when dosed orally to rats dogs and monkeys.
References (18)
- et al.
Preliminary biochemical characterization of two angiotensin II receptor subtypes
Biochemical Biophysical Research Communications
(1989) - et al.
Expression of Angiotensin II AT2 receptors in the rat skin during experimental wound healing
Peptides
(1992) - et al.
Characterization of BIBS 39 and BIBS 222: two new nonpeptide angiotensin II receptor antagonists
European Journal of Pharmacology
(1992) - et al.
Potent and Orally Active Triazolinone Angiotensin Ii Antagonists. Part 2. Heterocyclic And Related Acylsulfonamides
Abstracts of Papers, 206th Am. Chem. Soc. Natl. Mtg.
(August 22-27, 1993) - et al.
Quinazolinones as angiotensin II antagonists: Part 2. QSAR and in vivo characterization of AT1 selective AII antagonists
Bioorganic and Medicinal Chemistry Letters
(1993) - et al.
Inhibition of the renin angiotensin system in congestive heart failure
Current Drugs
(1992) - et al.
Losartan (DuP 753), an orally active nonpeptide angiotensin II receptor antagonist
Cardiovascular Drug Reviews
(1991) - et al.
Angiotensin II Receptor Subtypes
J. Hypertension
(1992) - et al.
Selective ligands reveal subtypes of angiotensin receptors in rat vasculature and brain
The Pharmacologists
(1989)
Cited by (29)
An overview of quinazolines: Pharmacological significance and recent developments
2018, European Journal of Medicinal ChemistryCitation Excerpt :Moreover compound L-162, 393 blocking AI1 pressor response in rats (1 mg/kg, i. v. or p. o.) with duration of action exceeding 6 h. This antagonist was superior to other quinazolinones when administered orally to dogs, and also showed oral activity in rhesus monkeys [165]. The result of quinazolinone biphenyl acylsulfonamides 211 (Fig. 40) clearly indicated that, with similar AT1 receptor binding affinities acylsulfonamides are potent AII antagonists than corresponding tetrazole derivatives.
Discovery of Nonpeptide, Selective AT<inf>2</inf> Receptor Agonists
2015, The Protective Arm of the Renin Angiotensin System (RAS): Functional Aspects and Therapeutic ImplicationsAngiotensin II receptor type 1 (AT<inf>1</inf>) selective nonpeptidic antagonists - A perspective
2010, Bioorganic and Medicinal ChemistryCitation Excerpt :The presence of lipophilic substituents at 6th position of quinazoline decides the affinity of a compound for both AT1 and AT2 as seen in L-159,689240 (165) and L-161,638241 (167) (AT1/AT2, 1:3000). The incorporation of a sulfonylcarbamate group in place of tetrazole along with 6th substitution provides further enhancement in the AT2 binding affinity as observed in L-162,393242 (166) and L-163,579,243 (168) (AT1:AT2 nearly 1:2). Compound (169) having quinazoline ring connected to the biphenyl ring through sulfur was synthesized and evaluated for AT1 receptor antagonistic activity.
Development of CoMFA models of affinity and selectivity to angiotensin II type-1 and type-2 receptors
2007, Journal of Molecular Graphics and ModellingPeptidomimetics in drug design
1997, Advances in Drug ResearchIn vivo pharmacology of an angiotensin AT<inf>1</inf> receptor antagonist with balanced affinity for angiotensin AT<inf>2</inf> receptors
1995, European Journal of Pharmacology