Abstract：
:Replacing one amide bond in macrocyclic renin inhibitors of the general structure 1 and 2 with an ester linkage gave glutamate-derived inhibitors 3 and serine-derived inhibitors 4. While this oxygen-for-nitrogen exchange had little effect on potency in the glutamate series, potency was dramatically increased in the serine series. In this series, the 14-membered ring compounds proved to be more potent than the corresponding 13-membered ring derivatives. Substitution of the ring at the position corresponding to P2' generally increased potency. The absolute configuration at this center was shown to be R for the 4-morpholinomethyl derivative (4o), both by asymmetric synthesis and X-ray crystallography. Replacing the "Boc-Phe" moiety of inhibitor 4o with a variety of substituents led to subnanomolar inhibitors, one of which (the "3(S)-quinuclidinyl-Phe" derivative 33) lowered blood pressure 20 mmHg and completely inhibited plasma renin activity for 6 h in sodium-depleted rhesus monkeys. This compound proved to have limited bioavailability (1% in rats) due to cleavage of the serine ester bond and rapid hepatic extraction.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Weber AE,Steiner MG,Krieter PA,Colletti AE,Tata JR,Halgren TA,Ball RG,Doyle JJ,Schorn TW,Stearns RAdoi
10.1021/jm00099a004keywords:
subject
Has Abstract,Author List Incompletepub_date
1992-10-16 00:00:00pages
3755-73issue
21eissn
0022-2623issn
1520-4804journal_volume
35pub_type
杂志文章abstract：:Overexpression of the HER2 receptor is observed in about 30% of breast and ovarian cancers and is often associated with an unfavorable prognosis. We have recently designed an anti-HER2 peptide (AHNP) based on the structure of the CDR-H3 loop of the anti-HER2 rhumAb 4D5 and showed that this peptide can mimic some funct...
journal_title：Journal of medicinal chemistry
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更新日期：2001-08-02 00:00:00
abstract：:The ruthenium complex, trans-[Ru(Bz)(NH 3) 4SO 2](CF 3SO 3) 2 1, Bz = benznidazole ( N-benzyl-2-(2-nitro-1 H-imidazol-1-yl)acetamide), is more hydrosoluble and more active (IC 50try/1 h = 79 +/- 3 microM) than free benznidazole 2 (IC 50try/1 h > 1 mM). 1 also exhibits low acute toxicity in vitro (IC 50macrophages > 1 ...
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pub_type： 杂志文章
doi：10.1021/jm701306r
更新日期：2008-07-24 00:00:00
abstract：:All of the selective COX-2 inhibitors described to date inhibit the isoform by binding tightly but noncovalently at the substrate binding site. Recently, we reported the first account of selective covalent modification of COX-2 by a novel inactivator, 2-acetoxyphenyl hept-2-ynyl sulfide (70) (Science 1998, 280, 1268-1...
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doi：10.1021/jm980303s
更新日期：1998-11-19 00:00:00
abstract：:The synthesis and evaluation of a refined series of alpha-ketoheterocycles based on the oxazole 2 (OL-135) incorporating systematic changes in the central heterocycle bearing a key set of added substituents are described. The nature of the central heterocycle, even within the systematic and minor perturbations explore...
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abstract：:We herein report phosphorodiamidates as a significant new phosphate prodrug motif. Sixty-seven phosphorodiamidates are reported of two 6-O-alkyl 2'-C-methyl guanosines, with significant variation in the diamidate structure. Both symmetrical and asymmetric phosphorodiamidates are reported, derived from various esterifi...
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更新日期：1994-05-27 00:00:00
abstract：:The ester methyl [4-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy]phenoxy]acetate (1) (R1 = OMe) had previously been identified as the most interesting member of a series of selective beta 3-adrenergic agonists of brown adipose tissue and thermogenesis in the rat. In vivo it acts mainly via the related acid 1 (R1 = OH)....
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00088a010
更新日期：1992-05-15 00:00:00
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pub_type： 杂志文章
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更新日期：1987-09-01 00:00:00
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journal_title：Journal of medicinal chemistry
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journal_title：Journal of medicinal chemistry
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更新日期：1986-02-01 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
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更新日期：2000-04-20 00:00:00
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更新日期：2004-06-03 00:00:00
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更新日期：2001-04-26 00:00:00
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更新日期：2011-10-27 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
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更新日期：1990-09-01 00:00:00
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更新日期：1995-07-21 00:00:00
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更新日期：1987-03-01 00:00:00
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