Abstract:
:We report the solid-phase synthesis and antagonistic potencies of 25 analogues (1-25) of [1-(beta-mercapto-beta,beta-pentamethylenepropionic acid),2-O-ethyl-D-tyrosine,4-valine]arginine-vasopressin (d(CH2)5D-Tyr(Et)2-VAVP) (A) and of the related Ile4 (D) and [D-Phe2,Ile4] (E) analogues, potent antagonists of the antidiuretic (V2-receptor) and of the vasopressor (V1a-receptor) responses to arginine-vasopressin (AVP). Six of these peptides (1, 13, 17, 19, 21, and 23) have the Pro-Arg-Gly-NH2 tripeptide side chain fully or partially replaced or extended by ethylenediamine (Eda). The remaining 19 peptides have L- or D-amino acids retrolinked to these six C-terminal Eda peptides. Peptides 1, 13, 17, and 19 all have the ring structure of (A). Their side-chain structures are as follows: 1, Eda; 13, Pro-Eda; 17, Pro-Arg-Eda; 19, Arg-Gly-Eda. Peptide 21 is the Pro-Arg-Eda analogue of D; peptide 23 is the Pro-Arg-Gly-Eda analogue of E. Peptide 2 is the retro-Arg analogue of 1. Its side-chain structure is Eda<--Arg. Peptides 3-6 are analogues of 2 which have the D-Tyr-(Et)2 residue replaced by L-Tyr(Et)2 (3), D-Phe2 (4), D-Ile2 (5), or D-Leu2 (6), respectively. Peptides 7-12 are analogues of 2 which have the C-terminal retro-Arg replaced in retrofashion by D-Arg (7), Gly (8), Orn (9), D-Orn (10), D-Lys (11), or Arg-Arg (12). Peptides 14-16 have D-Orn (14), D-Lys (15), and D-Arg (16) retrosubstituted to peptide 13. Peptides 18, 20, and 22 are the retro-Arg-substituted analogues of 17, 19, and 21, respectively. Peptides 24 and 25 have Val and D-Val in retrolinkage with 23, respectively. All 25 peptides were examined for agonistic and antagonistic potencies in AVP V2/V1a assays. With the exception of peptides 5 and 6, all exhibit potent anti-V1a antagonism, with anti-V1a pA2 values in the range 7.64-8.33.(ABSTRACT TRUNCATED AT 400 WORDS)
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Manning M,Przybylski J,Grzonka Z,Nawrocka E,Lammek B,Misicka A,Cheng LL,Chan WY,Wo NC,Sawyer WHdoi
10.1021/jm00099a018keywords:
subject
Has Abstractpub_date
1992-10-16 00:00:00pages
3895-904issue
21eissn
0022-2623issn
1520-4804journal_volume
35pub_type
杂志文章abstract::Squalestatins without either the hydroxy group at C-4 or the carboxylic acid at C-3 or C-4 were prepared and evaluated for their ability to inhibit rat liver microsomal squalene synthase (SQS) in vitro. These modifications were well tolerated for compounds with the 4,6-dimethyloctenoate ester at C-6 (S1 series). Howev...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm9504969
更新日期:1996-01-05 00:00:00
abstract::Regression analysis of the potency of inhibition of monoamine oxidase by 47 propynylamines revealed that there are three determinants of inhibitory potency: (1) the smallest substituent on the nitrogen must be methyl or hydrogen in order for any activity to be observed; (2) potency is parabolically related to pKa-the ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00243a004
更新日期:1975-09-01 00:00:00
abstract::The novel lead bis(1H-2-indolyl)methanone inhibits autophosphorylation of platelet-derived growth factor (PDGF) receptor tyrosine kinase in intact cells. Various substituents in the 5- or 6-position of one indole ring increase or preserve potency, whereas most modifications of the ring structures and of the methanone ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm010988n
更新日期:2002-02-28 00:00:00
abstract::A series of indolylsulfonylcinnamic hydroxamates has been synthesized. Compound 12, (E)-3-(3-((1H-pyrrolo[2,3-b]pyridin-1-yl)sulfonyl)phenyl)-N-hydroxyacrylamide, which has a 7-azaindole core cap, was shown to have antiproliferative activity against KB, H460, PC3, HSC-3, HONE-1, A549, MCF-7, TSGH, MKN45, HT29, and HCT...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm401899x
更新日期:2014-05-22 00:00:00
abstract::A theoretically rigorous and computationally tractable methodology for the prediction of the free energies of binding of protein-ligand complexes is presented. The method formulated involves developing molecular dynamics trajectories of the enzyme, the inhibitor, and the complex, followed by a free energy component an...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm010175z
更新日期:2001-12-06 00:00:00
abstract::Several N(1)-arylalkylpolyamines containing various aromatic ring systems were synthesized as their respective HCl salts. The N(1)-substituents evaluated ranged in size from N(1)-benzyl, N(1)-naphthalen-1-ylmethyl, N(1)-2-(naphthalen-1-yl)ethyl, N(1)-3-(naphthalen-1-yl)propyl, N(1)-anthracen-9-ylmethyl, N(1)-2-(anthra...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0497040
更新日期:2004-11-18 00:00:00
abstract::Five dipeptidomimetic-based model prodrugs containing ketomethylene amide bond replacements were synthesized from readily available alpha,beta-unsaturated gamma-ketoesters. The model drug (BnOH) was attached to the C-terminus or to one of the side chain positions of the dipeptidomimetic. The stability, the affinity fo...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm040780c
更新日期:2004-09-09 00:00:00
abstract::Following the observation that the activity of gonadotropin-releasing hormone III (GnRH-III) in the suppression of growth of MDA-MB-231 and MCF-7 breast cancer cells surpasses that of GnRH and other analogs thereof, analogs of GnRH-III were synthesized to investigate the structural basis for the improved antitumor act...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm9700981
更新日期:1997-10-10 00:00:00
abstract::The chelating drugs BAL (2,3-dimercaptopropanol), EDTA (ethylenediaminetetraacetic acid), and penicillamine (2-amino-3-mercapto-3-methylbutanoic acid), which are used for metal poisoning, are toxic and there is a real need for alternatives, especially for severe cases. A novel approach for treatment of heavy-metal poi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00142a028
更新日期:1981-10-01 00:00:00
abstract::A short series of the title compounds was prepared and evaluated for antiallergic activity in the rat passive cutaneous anaphylaxis screen. All but the two N-methylated derivatives were active in this screen by the intravenous route, the most potent being the symmetrical dimethyl compound, 4,9-dihydro-6,7-dimethyl-4,9...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00359a016
更新日期:1983-05-01 00:00:00
abstract::The effect of substitution of the pyrrolo- and indolo-N atoms in tetrahydronaltrindole (TNTI), tetrahydrooxymorphindole (TOMI), and 17-cyclopropylmethyl-3,14-dihydroxy-4,5-epoxy-4'-phenyl-6,7:2',3'-pyrrolomorphinan (4) is reported. In opioid functional assays 4 were potent deltaopioid receptor (DOR) antagonists while ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm040817t
更新日期:2004-12-16 00:00:00
abstract::Acyl carrier protein synthase (AcpS) catalyzes the transfer of the 4'-phosphopantetheinyl group from the coenzyme A to a serine residue in acyl carrier protein (ACP), thereby activating ACP, an important step in cell wall biosynthesis. The structure-based design of novel anthranilic acid inhibitors of AcpS, a potentia...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm050523n
更新日期:2005-12-15 00:00:00
abstract::A series of [(heteroarylamino)phenyl]alkanoic acids having pyridine, quinoline, or pyrimidine as the heteroaryl moiety was prepared as potential antiinflammatory agents. Among them, 2-[4-(2-pyridylamino)phenyl]propionic acid (14b) showed excellent antiinflammatory and analgesic activities with less tendency to cause g...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00356a019
更新日期:1983-02-01 00:00:00
abstract::As part of our studies on the design of agonists of the luteinizing hormone-releasing hormone (LH-RH), we have synthesized the [des-Gly-NH2(10)]-LH-RH N-methylhydrazide (1), the corresponding thiosemicarbazide (2), and the N-formyl- (3) N-acetyl- (4) and N-(trifluoroacetyl)hydrazide (5). Analogue 1 may be regarded as ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00134a021
更新日期:1981-02-01 00:00:00
abstract::Small-molecule fluorescence imaging in the second near-infrared (NIR-II, 1000-1700 nm) window has gained increasing interest in clinical application. Till now, very few studies have been exploited in the small-molecule fluorophores with both excitation and emission in the NIR-II window. Inspired by the indocyanine gre...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.8b01682
更新日期:2019-02-28 00:00:00
abstract::The synthesis of chiral 1,5-benzothiazepines 2a-c, 14a-c, 15c, and 16a prepared from cysteine is described. In vitro inhibition of angiotensin converting enzyme (ACE) is reported for each compound. Compound 2c was the most potent in vitro having an IC50 of 2.95 nM. The ester of 2c, i.e. 14c, was found to inhibit the A...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00148a024
更新日期:1985-10-01 00:00:00
abstract::A series of renin inhibitors with novel modifications at the P2 site has been prepared. Structure-activity relationships reveal that for a particular P2 fragment the in vitro potency is highly dependent on the nature of the P2' portion in addition to the P1-P1' group. The length of the P2 side chain and choice of epsi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00108a004
更新日期:1991-04-01 00:00:00
abstract::The oxazolidinones are a new class of synthetic antibacterials effective against a broad range of pathogenic Gram-positive bacteria, including multi-drug-resistant strains. Linezolid is the first drug from this class to reach the market and has become an important new option for the treatment of serious infections, pa...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm058204j
更新日期:2005-07-28 00:00:00
abstract::We describe the synthesis of gramine derivatives and their pharmacological evaluation as multipotent drugs for the treatment of Alzheimer's disease. An innovative multitarget approach is presented, targeting both voltage-gated Ca(2+) channels, classically studied for neurodegenerative diseases, and Ser/Thr phosphatase...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.6b00478
更新日期:2016-07-14 00:00:00
abstract::The synthesis of 5-(arylacetyl)-4-[(alkylamino)methyl]furo[3,2-c] pyridines (16-23, 26, 27) and their activities as kappa-opioid receptor agonists are described. kappa-Agonist potency was particularly sensitive to the nature of the basic moiety. In particular, in the rabbit vas deferens (kappa-specific tissue), the 3-...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00040a004
更新日期:1994-07-08 00:00:00
abstract::In previous studies we demonstrated that lipophilic (99m)Tc-labeled LTB4 antagonist 1 (RP517) accumulated in infectious foci in rabbits, but hepatobiliary clearance hampered imaging of abdominal lesions. We now report the use of cysteic acid as a pharmacokinetic modifier to improve the water solubility and renal clear...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm050383h
更新日期:2005-10-06 00:00:00
abstract::Developing Janus kinase 2 (Jak2) inhibitors has become a significant focus for small molecule drug discovery programs in recent years due to the identification of a Jak2 gain-of-function mutation in the majority of patients with myeloproliferative disorders (MPD). Here, we describe the discovery of a thienopyridine se...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm200911r
更新日期:2011-12-22 00:00:00
abstract::The sphingoid base derived class of lipids (sphingolipids) is a family of interconverting molecules that play key roles in numerous structural and signaling processes. The biosynthetic pathway of the sphingolipids affords many opportunities for therapeutic intervention: targeting the ligands directly, targeting the va...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1021/acs.jmedchem.6b01575
更新日期:2017-07-13 00:00:00
abstract::The Free-Wilson equations are derived for the case of symmetrical substitution and are applied, in four modifications, to in vitro inhibitory activity of 77 organic disulfides against Histoplasma capsulatum. Substituent constants are listed to aid in the design of new inhibitory agents against this human pathogen (and...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00238a004
更新日期:1975-04-01 00:00:00
abstract::The cyclic somatostatin analogue cyclo[Pro(1)-Phe(2)-D-Trp(3)-Lys(4)-Thr(5)-Phe(6)] (L-363,301) displays high biological activity in inhibiting the release of growth hormone, insulin, and glucagon. According to the sequence of L-363,301, we synthesized a number of cyclic hexa- and pentapeptides containing nonnatural a...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm049500j
更新日期:2005-04-21 00:00:00
abstract::Dimethylallylguanidine, also known as galegine, isolated from Galega officinalis, has been shown to have weight reducing properties in vivo. Substitution of the guanidine group with an N-cyano group and replacement of guanidine with amidine, pyrimidine, pyridine, or the imidazole moieties removed the weight reducing p...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm8011933
更新日期:2009-06-11 00:00:00
abstract::Activators of nuclear factor-erythroid 2-related factor 2 (NRF2) could lead to promising therapeutics for prevention and treatment of oxidative stress and inflammatory disorders. Ubiquitination and subsequent degradation of the transcription factor NRF2 is mediated by Kelch-like ECH-associated protein-1 (KEAP1). Inhib...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.8b01133
更新日期:2018-09-13 00:00:00
abstract::1, 8-Disubstituted derivatives of adenosine cyclic 3', 5'-phosphate (cAMP) were synthesized by N-oxidation or N-methylation of previously reported 8-substituted cAMP derivatives to yield 8-bromoadenosine cyclic 3', 5'-phosphate 1-oxide and 8-(benzylthio)-1-methyladenosine cyclic 3', 5'-phosphate. Substituents were int...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00225a017
更新日期:1976-03-01 00:00:00
abstract::Structure-based strategy was employed to design flavonoid compounds to mimic the Bim BH3 peptide as a new class of inhibitors of the anti-apoptotic Bcl-2 proteins. The most potent compound, 4 (BI-33), binds to Bcl-2 and Mcl-1 with Ki values of 17 and 18 nM, respectively. Compound 4 inhibits cell growth in the MDA-MB-2...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm070383c
更新日期:2007-07-12 00:00:00
abstract::The mechanism of action of a general class of mechanism-based inhibitors of serine proteases, including human neutrophil elastase (HNE), has been elucidated by determining the X-ray crystal structure of an enzyme-inhibitor complex. The captured intermediate indicates that processing of inhibitor by the enzyme generate...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm700966p
更新日期:2008-04-10 00:00:00