Abstract:
:This report describes the discovery of RAD140, a potent, orally bioavailable, nonsteroidal selective androgen receptor modulator (SARM). The characterization of RAD140 in several preclinical models of anabolic androgen action is also described.
journal_name
ACS Med Chem Lettjournal_title
ACS medicinal chemistry lettersauthors
Miller CP,Shomali M,Lyttle CR,O'Dea LS,Herendeen H,Gallacher K,Paquin D,Compton DR,Sahoo B,Kerrigan SA,Burge MS,Nickels M,Green JL,Katzenellenbogen JA,Tchesnokov A,Hattersley Gdoi
10.1021/ml1002508subject
Has Abstractpub_date
2010-12-02 00:00:00pages
124-9issue
2issn
1948-5875journal_volume
2pub_type
杂志文章abstract::The phenethylamine backbone is a privileged substructure found in a wide variety of G protein-coupled receptor (GPCR) ligands. This includes both endogenous neurotransmitters and active pharmaceutical agents. More than 20 structurally unique heterocyclic phenethylamine derivatives were broadly evaluated for GPCR affin...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.9b00225
更新日期:2019-09-23 00:00:00
abstract::A high throughput screen was developed to identify novel, nonsteroidal RORα agonists. Among the validated hit compounds, the 4-(4-(benzyloxy)phenyl)-5-carbonyl-2-oxo-1,2,3,4-tetrahydropyrimidine scaffold was the most prominent. Among the numerous analogues tested, compounds 8 and 9 showed the highest activity. Key str...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml300471d
更新日期:2013-04-10 00:00:00
abstract::A new class of 4-aminoquinolines was synthesized and evaluated in vitro for antiplasmodial activity against both the chloroquine-sensitive (3D7) and -resistant (K1 and W2) strains. The most active compounds 3c-3e had acceptable cytotoxicity but showed strong inhibition toward a panel of cytochrome P450 enzymes in vitr...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400311r
更新日期:2013-10-01 00:00:00
abstract::Inhibition of the lipid kinase PI3Kδ is a promising principle to treat B and T cell driven inflammatory diseases. Using a scaffold deconstruction-reconstruction strategy, we identified 4-aryl quinazolines that were optimized into potent PI3Kδ isoform selective analogues with good pharmacokinetic properties. With compo...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.6b00119
更新日期:2016-06-02 00:00:00
abstract::Minibodies show rapider blood clearance than IgGs due to smaller size that improves target-to-background ratio (TBR) in in vivo imaging. Additionally, the ability to activate an optical probe after binding to the target greatly improves the TBR. An optical imaging probe based on a minibody against prostate-specific me...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400533y
更新日期:2014-01-17 00:00:00
abstract::A novel peroxisome proliferator-activated receptor (PPAR) α/δ dual agonist 5c was developed with an EC50 of 8 nM for PPARα, 5 nM for PPARδ, and >300-fold selectivity against PPARγ (EC50 = 2939 nM), respectively. Further ADME and pharmacokinetic studies indicated 5c possessed distinguished in vitro and in vivo profiles...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.9b00189
更新日期:2019-06-24 00:00:00
abstract::P-glycoprotein (Pgp) is capable of recognizing and transporting a wide range of chemically diverse compounds in vivo. Overcoming Pgp-mediated efflux can represent a significant challenge when penetration into the central nervous system is required or within the context of developing anticancer therapies. While numerou...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml300314h
更新日期:2012-11-06 00:00:00
abstract::Highly toxic bacterial ionophores are commonly used in veterinary medicine, but their therapeutic index is too narrow for human usage. With the goal of developing ionophores with a broader therapeutic index, we constructed highly derivatized synthetic ionophores. The toxicities of crown ether host-rotaxanes (CEHR's) a...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml3003204
更新日期:2013-01-10 00:00:00
abstract::In addition to its therapeutic value as a chemotherapy drug, gemcitabine is of ongoing interest to the scientific community for its broad-spectrum antiviral activity. Herein the synthesis of 4'-methoxy- and 4'-fluoro-substituted gemcitabine analogues along with their phosphoramidate prodrugs is described. Among these ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.0c00485
更新日期:2020-12-09 00:00:00
abstract::Molecular characterization of the binding epitope of IL-23R and its cognate cytokine IL-23 is paramount to understand the role in autoimmune diseases and to support the discovery of new inhibitors of this protein-protein interaction. Our results revealed that HDX-MS was able to identify the binding epitope of IL-23R:I...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00255
更新日期:2018-08-01 00:00:00
abstract::Current treatment of toxoplasmosis targets the parasite's folate metabolism through inhibition of dihydrofolate reductase (DHFR). The most widely used DHFR antagonist, pyrimethamine, was introduced over 60 years ago and is associated with toxicity that can be largely attributed to a similar affinity for parasite and h...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.6b00328
更新日期:2016-09-17 00:00:00
abstract::A new category of cationic meso-thiophenium porphyrins are introduced as possible alternatives to the popular meso-pyridinium porphyrins. Combinations of cationic porphyrins bearing meso-2-methylthiophenium and meso-4-hydroxyphenyl moieties T2(OH)2M (A2B2 type) and T(OH)3M (AB3 type) along with their zinc(II) complexe...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.0c00266
更新日期:2020-09-10 00:00:00
abstract::Structural modifications to the coumarin core and benzamide side chain of novobiocin have successfully transformed the natural product from a selective DNA gyrase inhibitor into a potent inhibitor of the Hsp90 C-terminus. However, no SAR studies have been conducted on the noviose appendage, which represents the rate-l...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml100070r
更新日期:2010-07-13 00:00:00
abstract::A focused multiply N-methylated library of a cyclic hexapeptidic somatostatin analogue: MK678 cyclo(-MeAYwKVF-) was generated, which resulted in the unexpected observation of an efficacious tetra-N-methylated analogue, cyclo(-MeAYMewMeKVMeF-) with a potent inhibitory action on sensory neuropeptide release in vitro and...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml200032v
更新日期:2011-04-04 00:00:00
abstract::Fluorescent biosensors constitute potent tools for probing biomolecules in their natural environment and for visualizing dynamic processes in complex biological samples, living cells, and organisms. They are well suited for highlighting molecular alterations associated with pathological disorders, thereby offering mea...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400472e
更新日期:2013-12-18 00:00:00
abstract::A series of novel selenides bearing benzenesulfonamide moieties was synthesized and investigated for their inhibition on six human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms such as the physiologically relevant hCA I, II, VA, VB, VII, and IX and the X-ray complex in adduct with hCA II for some of them investigat...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00076
更新日期:2018-04-09 00:00:00
abstract::The solution behavior of auranofin, Et3PAuCl and Et3PAuI, as well as their interactions with hen egg white lysozyme, single strand oligonucleotide, and ds-DNA were comparatively analyzed through NMR spectroscopy, ESI-MS, ethidium bromide displacement, DNA melting and viscometric tests. The cytotoxic effects toward re...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.7b00162
更新日期:2017-09-06 00:00:00
abstract::Modifications at the basic nitrogen of the benzomorphan scaffold allowed the development of compounds able to segregate physiological responses downstream of the receptor signaling, opening new possibilities in opioid drug development. Alkylation of the phenyl ring in the N-substituent of the MOR-agonist/DOR-antagonis...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.9b00549
更新日期:2020-01-28 00:00:00
abstract::A number of biologically active nucleoside analogues contain the adenine isostere 4-amino-pyrrolo[2,1-f][1,2,4]triazine connected to various sugar moieties through a C-C anomeric linkage. We employed palladium-catalyzed cross-coupling chemistry to promptly functionalize the 7-position of such a heterocyclic scaffold w...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.0c00269
更新日期:2020-07-09 00:00:00
abstract::Bone Morphogenetic Protein 1 (BMP1) inhibition is a potential method for treating fibrosis because BMP1, a member of the zinc metalloprotease family, is required to convert pro-collagen to collagen. A novel class of reverse hydroxamate BMP1 inhibitors was discovered, and cocrystal structures with BMP1 were obtained. T...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00173
更新日期:2018-07-02 00:00:00
abstract::This report describes the investigation of a series of 5,7-disubstituted imidazo[5,1-f][1,2,4]triazine inhibitors of insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR). Structure-activity relationship exploration and optimization leading to the identification, characterization, and pharmacologica...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml100178g
更新日期:2010-08-30 00:00:00
abstract::A series of alkylpyrimidine-4,6-diol derivatives were designed and synthesized as novel GRP84 agonists based on a high-throughput screening (HTS) hit 1. 6-Nonylpyridine-2,4-diol was identified as the most potent agonist of GPR84 reported so far, with an EC50 of 0.189 nM. These novel GPR84 agonists will provide valuabl...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.6b00025
更新日期:2016-03-30 00:00:00
abstract::The attachment of lipids to C- or N-terminally positioned lysine side-chain amino groups increases the activity of a short synthetic (Arg-Trp)3 antimicrobial peptide significantly, making these peptides even active against pathogenic Gram-negative bacteria. Thus, a peptide with strong activity against S. aureus (1.1-2...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml300148v
更新日期:2012-09-04 00:00:00
abstract::The N-methyl-d-aspartate receptor (NMDAR) is an ionotropic glutamate receptor, gated by the endogenous coagonists glutamate and glycine, permeable to Ca2+ and Na+. NMDAR dysfunction is associated with numerous neurological and psychiatric disorders, including schizophrenia, depression, and Alzheimer's disease. Recentl...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.6b00388
更新日期:2016-10-31 00:00:00
abstract::A series of oxyguanidine analogues of the cysteine protease inhibitor WRR-483 were synthesized and evaluated against cruzain, the major cysteine protease of the protozoan parasite Trypanosoma cruzi. Kinetic analyses of these analogues indicated that they have comparable potency to previously prepared vinyl sulfone cru...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.5b00336
更新日期:2015-12-15 00:00:00
abstract::A de novo hit-to-lead effort involving the redesign of benzimidazole-containing antagonists of the CXCR4 receptor resulted in the discovery of a novel series of 1,2,3,4-tetrahydroisoquinoline (TIQ) analogues. In general, this series of compounds show good potencies (3-650 nM) in assays involving CXCR4 function, includ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400183q
更新日期:2013-09-05 00:00:00
abstract::Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase that degrades the fatty acid amide family of signaling lipids, including the endocannabinoid anandamide. Genetic or pharmacological inactivation of FAAH leads to analgesic and anti-inflammatory phenotypes in rodents without showing the undesira...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml100190t
更新日期:2011-02-10 00:00:00
abstract::Cucurbit[7]uril (CB[7]) was found in vitro to sequester the neurotoxins MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and MPP(+) (N-methyl-4-phenylpyridine). The CB[7]/neurotoxin host-guest complexes were studied in detail with (1)H NMR, electrospray ionization mass spectrometry, UV-visible spectroscopic titrati...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.5b00372
更新日期:2015-10-16 00:00:00
abstract::In this paper, we describe the discovery and optimization of a series of noncovalent reversible epidermal growth factor receptor inhibitors of EGFRL858R/T790M/C797S. One of the most promising compounds, 25g, inhibited the enzymatic activity of EGFRL858R/T790M/C797S with an IC50 value of 2.2 nM. Cell proliferation assa...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00564
更新日期:2019-05-22 00:00:00
abstract::A novel selective benzoxazepin inhibitor of PI3Kδ has been discovered. Beginning from compound 3, an αPI3K inhibitor, we utilized structure-based drug design and computational analysis of dihedral torsion angles to optimize for PI3Kδ isoform potency and isoform selectivity. Further medicinal chemistry optimization of ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.7b00170
更新日期:2017-08-25 00:00:00