TRIAZOLINONES AS NONPEPTIDE ANGIOTENSIN-II ANTAGONISTS .1. SYNTHESIS AND EVALUATION OF POTENT 2,4,5-TRISUBSTITUTED TRIAZOLINONES

被引:38
作者
CHANG, LL [1 ]
ASHTON, WT [1 ]
FLANAGAN, KL [1 ]
STRELITZ, RA [1 ]
MACCOSS, M [1 ]
GREENLEE, WJ [1 ]
CHANG, RSL [1 ]
LOTTI, VJ [1 ]
FAUST, KA [1 ]
CHEN, TB [1 ]
BUNTING, P [1 ]
ZINGARO, GJ [1 ]
KIVLIGHN, SD [1 ]
SIEGL, PKS [1 ]
机构
[1] MERCK SHARP & DOHME LTD,W POINT,PA 19486
关键词
D O I
10.1021/jm00069a015
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of 2,4-dihydro-2,4,5-trisubstituted-3H-1,2,4-triazol-3-ones was prepared via several synthetic routes and evaluated as AII receptor antagonists in vitro and in vivo. The preferred compounds contained a [2'-(5-tetrazolyl)biphenyl-4-yl]methyl side chain at N4 and an n-butyl group at C5. A number of these bearing an alkyl or aralkyl substituent at N2 showed in vitro potency in the nanomolar range (rabbit aorta membrane receptor), and several of these, e.g., the 2,2-dimethyl-1-propyl analogue (54, IC50 = 2.1 nM), effectively blocked the AII pressor response in conscious rats with significant duration (2.5 h at 1 mg/kg orally for 54). Among analogues possessing aryl substituents at N2, ortho substitution on the phenyl moiety resulted in several derivatives with in vitro potency in the low nanomolar range. One of these, featuring a 2-(trifluoromethyl)phenyl substituent at N2 (25, IC50 = 1.2 nM), was effective at 1 mg/kg orally in the rat model, with a duration of >6 h. Implications for hydrophobic and hydrogen-bonding interactions with the AT1 receptor are discussed.
引用
收藏
页码:2558 / 2568
页数:11
相关论文
共 46 条
  • [21] Some amedines of the holocaine type II
    Hill, AJ
    Rabinowitz, I
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1926, 48 (01) : 732 - 737
  • [22] KANE JM, 1987, SYNTHESIS-STUTTGART, P912
  • [23] ANGIOTENSIN-CONVERTING ENZYME-INHIBITORS AND THEIR INFLUENCE ON INFLAMMATION, BRONCHIAL REACTIVITY AND COUGH - A RESEARCH REVIEW
    LINDGREN, BR
    ANDERSSON, RGG
    [J]. MEDICAL TOXICOLOGY AND ADVERSE DRUG EXPERIENCE, 1989, 4 (05): : 369 - 380
  • [24] SYNTHESIS AND X-RAY CRYSTAL-STRUCTURE OF A 2,4,5-TRISUBSTITUTED 1,2,4-TRIAZOLIN-3-ONE
    MADDING, GD
    SMITH, DW
    SHELDON, RI
    LEE, B
    [J]. JOURNAL OF HETEROCYCLIC CHEMISTRY, 1985, 22 (04) : 1121 - 1126
  • [25] POTENT, ORALLY ACTIVE IMIDAZO[4,5-B]PYRIDINE-BASED ANGIOTENSIN-II RECEPTOR ANTAGONISTS
    MANTLO, NB
    CHAKRAVARTY, PK
    ONDEYKA, DL
    SIEGL, PKS
    CHANG, RS
    LOTTI, VJ
    FAUST, KA
    CHEN, TB
    SCHORN, TW
    SWEET, CS
    EMMERT, SE
    PATCHETT, AA
    GREENLEE, WJ
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1991, 34 (09) : 2919 - 2922
  • [26] SPECIFIC COMPETITIVE INHIBITOR OF ANGIOTENSIN-II
    MARSHALL, GR
    VINE, W
    NEEDLEMA.P
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1970, 67 (03) : 1624 - &
  • [27] MOLECULAR SHAPE COMPARISON OF ANGIOTENSIN-II RECEPTOR ANTAGONISTS
    MASEK, BB
    MERCHANT, A
    MATTHEW, JB
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1993, 36 (09) : 1230 - 1238
  • [28] The preparation of orthoesters
    McElvain, SM
    Nelson, JW
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1942, 64 : 1825 - 1827
  • [29] OLINS GM, 1992, J PHARMACOL EXP THER, V261, P1037
  • [30] INHIBITION OF THE RENIN-ANGIOTENSIN SYSTEM - A NEW APPROACH TO THE THERAPY OF HYPERTENSION
    ONDETTI, MA
    CUSHMAN, DW
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1981, 24 (04) : 355 - 361