Abstract：
:Peroxisome proliferator-activated receptor alpha (PPARα) is expressed in retinal Müller cells, endothelial cells, and in retinal pigment epithelium; agonism of PPARα with genetic or pharmacological tools ameliorates inflammation, vascular leakage, neurodegeneration, and neovascularization associated with retinal diseases in animal models. As such, PPARα is a promising drug target for diabetic retinopathy and age-related macular degeneration. Herein, we report proof-of-concept in vivo efficacy in an streptozotocin-induced vascular leakage model (rat) and preliminary pharmacokinetic assessment of a first-generation lead 4a (A91). Additionally, we present the design, synthesis, and evaluation of second-generation analogues, which led to the discovery of 4u and related compounds that reach cellular potencies <50 nM and exhibit >2,700-fold selectivity for PPARα over other PPAR isoforms. These studies identify a pipeline of candidates positioned for detailed PK/PD and pre-clinical evaluation.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Dou X,Nath D,Shin H,Nurmemmedov E,Bourne PC,Ma JX,Duerfeldt ASdoi
10.1021/acs.jmedchem.9b01189subject
Has Abstractpub_date
2020-03-26 00:00:00pages
2854-2876issue
6eissn
0022-2623issn
1520-4804journal_volume
63pub_type
杂志文章abstract：:Because of the ambiguities of how to treat ionization in empirical equations which relate biological activity to partition coefficient by use of a (log P)2 term, a theoretical approach to the problem is proposed. Based on a simplified view of assays of potency following in vitro or continuous infusion administration o...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00230a012
更新日期：1976-08-01 00:00:00
abstract：:Deltorphin analogues were substituted by a series of achiral C alpha,alpha-dialkyl cyclic alpha-amino acids (1-aminocycloalkane-1-carboxylic acids, Ac chi c, where chi = a hexane, pentane, or propane cycloalkane ring) in position 2, 3, 4, or 2 and 3 in deltorphin C, and in position 2 in [Ac6c2,-des-Phe3]deltorphin C h...
journal_title：Journal of medicinal chemistry
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doi：10.1021/jm950490j
更新日期：1996-02-02 00:00:00
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journal_title：Journal of medicinal chemistry
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doi：10.1021/jm3003697
更新日期：2012-05-10 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm000936i
更新日期：2000-08-10 00:00:00
abstract：:A variety of N-(aminoalkanoyl)-S-acylcysteamine and N,N'-bis(aminoalkanoyl)cystamine salt derivatives were synthesized. Toxicity and radioprotective activity (as the dose reduction factor DRF) were determined in vivo on mice and compared to WR 2721 and S-acetylcysteamine hydrochloride. One of the most interesting comp...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00161a015
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00124a021
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abstract：:The (E)-8-benzylidene and (E)-8-(3,4-dichlorobenzylidene), 7-ketone derivatives, 5 and 6, of the synthetic opiate 2-methyl-5-(3-hydroxyphenyl)morphan [5-(3-hydroxyphenyl)-2-methyl-2-azabicyclo[3.3.1]nonane, 1], were synthesized from the 7-ketone derivatives 2 or 4 via the Claisen-Schmidt reaction. The corresponding en...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00045a022
更新日期：1994-09-16 00:00:00
abstract：:3',5'-Diamino-3',5'-dideoxythymidine (7) was synthesized via a nine-step synthesis from thymidine in good overall yield. 3'-Amino-3'-deoxythymidine (8) and 5'-amino-5'-deoxythymidine (12) were prepared with a minor modification of the procedure reported by Horwitz and co-workers. Although the 5'-amino analogue 12 had ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：
更新日期：1978-01-01 00:00:00
abstract：:1 (MTC-220), a conjugate of paclitaxel and a muramyl dipeptide analogue, has been synthesized as a novel agent of dual antitumor growth and metastasis activities. In vitro and in vivo tests show that 1 retains its ability to inhibit tumor growth. It is superior to paclitaxel in its ability to prevent tumor metastasis ...
journal_title：Journal of medicinal chemistry
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doi：10.1021/jm101577z
更新日期：2011-04-28 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00122a019
更新日期：1989-02-01 00:00:00
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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：:In order to investigate the structural requirements for gastroprotective activity in 6-[[1(S)-(3(S),4-dihydro-8- hydroxy-1-oxo-1H-2-benzopyran-3-yl)-3-methylbutyl]amino]-4(S),5(S)-dihydroxy 6-oxo-3(S)-ammoniohexanoate [AI-77-B, 1], a product of Bacillus pumilus AI-77, nine derivatives were prepared and then tested for...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00364a007
更新日期：1983-10-01 00:00:00
abstract：:Building on the previously and successfully applied hypothesis that stereochemical complication in the proximity of the critical cationic head of a cholinergic agonist would result in subtype selective compounds, we synthesized a series of chiral derivatives of furmethide and 5-methylfurmethide, with the aim of obtain...
journal_title：Journal of medicinal chemistry
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doi：10.1021/jm800145d
更新日期：2008-07-10 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00241a010
更新日期：1975-07-01 00:00:00
abstract：:The nuclear receptor Nurr1 can be activated by RXR via heterodimerization (RXR-Nurr1) and is a promising target for treating neurodegenerative diseases. We herein report the enantioselective synthesis and SAR of sterically constricted benzofurans at RXR. The established SAR, using whole cell functional assays, lead to...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b01702
更新日期：2016-02-11 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c00312
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journal_title：Journal of medicinal chemistry
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更新日期：2012-04-12 00:00:00
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doi：10.1021/acs.jmedchem.5b01441
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pub_type： 杂志文章
doi：10.1021/jm00173a028
更新日期：1990-11-01 00:00:00
abstract：:New 2-piperazinylbenzothiazole and 2-piperazinylbenzoxazole derivatives were prepared and tested as 5-HT3 receptor antagonists. Some of the new compounds antagonized the effect of 5-HT at the longitudinal muscle myenteric plexus (LMMP) preparation of the guinea pig ileum, and two benzothiazole derivatives, compounds 2...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00035a012
更新日期：1994-04-29 00:00:00
abstract：:Cyclopropylcarboxylic acids and esters and cyclopropylmethanols incorporating bromophenol moieties were investigated as inhibitors of the carbonic anhydrase enzyme (CA; EC 4.2.1.1). The cis- and trans-esters 5 and 6 were obtained from the reaction of 4-allyl-1,2-dimethoxybenzene (4) with ethyl diazoacetate, which afte...
journal_title：Journal of medicinal chemistry
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更新日期：2015-01-22 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00380a017
更新日期：1985-02-01 00:00:00
abstract：:In a previously described chimeric peptide, we reported that the multifunctional opioid/neuropeptide FF (NPFF) receptor agonist 0 (BN-9) produced antinociception for 1.5 h after supraspinal administration. Herein, four cyclic disulfide analogs containing l- and/or d-type cysteine at positions 2 and 5 were synthesized....
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pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c01367
更新日期：2020-12-24 00:00:00
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doi：10.1021/jm058003f
更新日期：2005-06-30 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm980077m
更新日期：1998-07-02 00:00:00
abstract：:A computational chemistry study has been performed on a series of tetrahydropyrimidine-2-ones (THPs) as HIV-1 protease (HIV-1 PR) inhibitors. The present investigation focuses on the correlation of inhibitor-enzyme complexation energies (E(compl)), inhibitor solvation energies E(solv)[I], and both polar and nonpolar b...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm010417v
更新日期：2002-02-14 00:00:00
abstract：:Chemical investigations leading to the construction of bis(bioreductive) alkylating agents having both conformationally restricted and mobile spacer regions are described. Two targets having the conformationally mobile ethylene spacer group, namely, 2,2'-ethylenebis[6-(hydroxymethyl)-p-benzoquinone] diacetate (3b) and...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00366a004
更新日期：1983-12-01 00:00:00
abstract：:The hPepT1-mediated transport properties of a series of 11 synthesized beta- and gamma-peptides have been studied in Caco-2 cells. The results show that several of the compounds interact with the peptide transporter, but only two beta-dipeptides act as substrates and are transported across the cell monolayers. These t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm070148u
更新日期：2007-10-18 00:00:00
