Abstract:
:A series of potent PDGFR inhibitors has been identified. The series was optimized for duration of action in the lung. A novel kinase occupancy assay was used to directly measure target occupancy after i.t. dosing. Compound 25 shows 24 h occupancy of the PDGFR kinase domain, after a single i.t. dose and has efficacy at 0.03 mg/kg, in the rat moncrotaline model of pulmonary arterial hypertension. Examination of PK/PD data from the optimization effort has revealed in vitro:in vivo correlations which link duration of action in vivo with low permeability and high basicity and demonstrate that nonspecific binding to lung tissue increases with lipophilicity.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Shaw DE,Baig F,Bruce I,Chamoin S,Collingwood SP,Cross S,Dayal S,Drückes P,Furet P,Furminger V,Haggart D,Hussey M,Konstantinova I,Loren JC,Molteni V,Roberts S,Reilly J,Saunders AM,Stringer R,Sviridenko L,Thomas M,doi
10.1021/acs.jmedchem.6b00703subject
Has Abstractpub_date
2016-09-08 00:00:00pages
7901-14issue
17eissn
0022-2623issn
1520-4804journal_volume
59pub_type
杂志文章abstract::This paper describes the chemical synthesis and CCK-B and CCK-A receptor binding affinities of a series of compounds in which the central amide bond of the CCK-B "dipeptoid" ligand tricyclo[3.3.1.1(3,7)]dec-2-yl [R-(R*,S*)]-[2-[[1-(hydroxymethyl)- 2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-2-oxoethyl]carb amate (4) ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00086a017
更新日期:1992-04-17 00:00:00
abstract::The synthesis and some biological activities of [4-beta-(2-thienyl)-L-alanine]oxytocin are reported. This analogue has been studied in an ongoing exploration of the biological effects of introducing amino acid residues with bulky hydrophobic side chains into the second corner position of the beta turn present in the c...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00199a022
更新日期:1978-01-01 00:00:00
abstract::A new high-affinity thyroid hormone antagonist 6 with druglike properties was designed and synthesized. The compound behaved as an antagonist in a cell transactivation assay, and in a first in vivo experiment in rats. ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm060521i
更新日期:2006-11-16 00:00:00
abstract::The kinase PIM-1 plays a pivotal role in cytokine signaling and is implicated in the development of a number of tumors. The three-dimensional structure of PIM-1 is characterized by an unique hinge region which lacks a second hydrogen bond donor and makes it particularly important to determine how inhibitors bind to th...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0504858
更新日期:2005-12-01 00:00:00
abstract::The regulation of lipid metabolism and it's effect on glucose control and diabetes has received intense interest. Hormone-sensitive lipase (HSL) is a vital enzyme in lipid metabolism. A series of novel pyrrolopyrazinediones has been discovered that demonstrate submicromolar activity both in the enzyme assay and in a (...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm020460y
更新日期:2003-03-27 00:00:00
abstract::A series of dithiocarbamates were prepared by reaction of primary/secondary amines with carbon disulfide in the presence of bases. These compounds were tested for the inhibition of four human (h) isoforms of the zinc enzyme carbonic anhydrase, CA (EC 4.2.1.1), hCA I, II, IX, and XII, involved in pathologies such as gl...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm300031j
更新日期:2012-02-23 00:00:00
abstract::Procedures were developed for the synthesis of exo-(2'-chloro-5-pyridinyl)-7-(endo and exo)-amino[2.2.1]heptanes (3a and 3b). The compounds were evaluated for binding to the alpha4beta2 and alpha7 nicotinic acetylcholine receptors (nAChRs), for pharmacological activity in the mouse tail-flick and hot-plate assays, and...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm058243v
更新日期:2005-11-17 00:00:00
abstract::Ketanserin is the prototypic 5-HT2 serotonin antagonist; although it has been an important tool for the study of serotonin pharmacology, it has had relatively little impact on drug design because remarkably little is known about its structure-affinity relationships. Furthermore, ketanserin also binds at 5-HT1C recepto...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00104a017
更新日期:1992-12-25 00:00:00
abstract::By screening an epigenetic compound library, we identified that UNC0638, a highly potent inhibitor of the histone methyltransferases G9a and GLP, was a weak inhibitor of SPIN1 (spindlin 1), a methyllysine reader protein. Our optimization of this weak hit resulted in the discovery of a potent, selective, and cell-activ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.9b00522
更新日期:2019-10-24 00:00:00
abstract::Tacrine and PBT2 (an 8-hydroxyquinoline derivative) are well-known drugs that inhibit cholinesterases and decrease beta-amyloid (Abeta) levels by complexation of redox-active metals, respectively. In this work, novel tacrine-8-hydroxyquinoline hybrids have been designed, synthesized, and evaluated as potential multifu...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm100329q
更新日期:2010-07-08 00:00:00
abstract::A previously outlined general procedure for preparing various 3-substituted cephalosporins from the penicillin nucleus has been used, with modifications where required, to prepare a series of analogues of cephalexin with various substituents in the 3-methyl group. The 3-substituents most conducive to broad-spectrum an...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00218a019
更新日期:1977-08-01 00:00:00
abstract::New chemotherapeutics are urgently needed to combat malaria. We previously reported on a novel series of antimalarial, ethylenediamine-based inhibitors of protein farnesyltransferase (PFT). In the current study, we designed and synthesized a series of second generation inhibitors, wherein the core ethylenediamine scaf...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm800113p
更新日期:2008-09-11 00:00:00
abstract::The drugs lenalidomide and pomalidomide bind to the protein cereblon, directing the CRL4-CRBN E3 ligase toward the transcription factors Ikaros and Aiolos to cause their ubiquitination and degradation. Here we describe CC-220 (compound 6), a cereblon modulator in clinical development for systemic lupus erythematosis a...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.6b01921
更新日期:2018-01-25 00:00:00
abstract::Analogues of the potent inhibitor of choline acetyltransferase (CAT) (E)-4-(1-naphthylvinyl)pyridine methiodide were synthesized and evaluated for their ability to inhibit CAT and protect against nerve agent intoxication. Several compounds, notably (E)-1-(2-hydroxyethyl)-(1-naphthylvinyl)pyridinium bromide (3), (E)-1-...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00399a022
更新日期:1988-04-01 00:00:00
abstract::While adding the structural features that are more favored by on-target activity is the more common strategy in selectivity optimization, the opposite strategy of subtracting the structural features that contribute more to off-target activity can also be very effective. Reported here is our successful effort of improv...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b00033
更新日期:2017-03-09 00:00:00
abstract::The synthesis, characterization, inhibitory activity against topoisomerase I, and biological evaluation of a series of oligopeptide-substituted bisindolylmaleimides 7-12 are described. Compounds 7-9, which contain a basic C-terminus function such as (dimethylamino)propyl and bind to DNA with C(50) values of 200, 160, ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm950465d
更新日期:1996-03-01 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
pub_type: 杂志文章
doi:10.1021/jm950490j
更新日期:1996-02-02 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
pub_type: 杂志文章
doi:10.1021/jm501573b
更新日期:2015-01-22 00:00:00
abstract::A series of 2,3-dihydrobenzofuran-5-acetic acids and related compounds was prepared as potential antiinflammatory agents. As measured by the carrageenan-induced edema method for the preliminary screening test, introduction of a methyl group alpha to the acetic acid function enhanced the antiinflammatory activity, and ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00224a020
更新日期:1976-02-01 00:00:00
abstract::Mycophenolic alcohol (MPAlc), obtained by reduction of the carboxylic group of mycophenolic acid (MPA), was coupled with 2',3'-O-isopropylideneadenosine 5'-methylenebis(phosphonate) (4) in the presence of diisopropylcarbodiimide (DIC) to give P1-(2',3'-O-isopropylideneadenosin-5'-yl)-P2-(mycophenolic alcohol-6'-yl)met...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm970705k
更新日期:1998-02-12 00:00:00
abstract::The perceived and actual burden of false positives in high-throughput screening has received considerable attention; however, few studies exist on the contributions of distinct mechanisms of nonspecific effects like chemical reactivity, assay signal interference, and colloidal aggregation. Here, we analyze the outcome...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm901070c
更新日期:2010-01-14 00:00:00
abstract::A series of balanol analogs in which the perhydroazepine ring and the p-hydroxybenzamide moiety were combined into an acyclic linked unit have been prepared and evaluated for their inhibitory properties against the serine/threonine kinase PKC. Several low-micromolar to low-nanomolar inhibitors of the alpha, beta I, be...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm960581w
更新日期:1996-12-20 00:00:00
abstract::We have previously shown that the 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor agonist, 2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA, 2), binds to AMPA receptors in a manner different from that of AMPA (1) itself and that 2, in contrast to 1, also binds to kainic acid re...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0003586
更新日期:2000-12-14 00:00:00
abstract::A new, highly potent, selective, and water-soluble antagonist of the hA(3) adenosine receptor was synthesized and tested in binding and functional assays. Compound 4 (5-[[(4-pyridyl)amino]carbonyl]amino-8-methyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine hydrochloride) displayed high water solubility (...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm020974x
更新日期:2002-08-15 00:00:00
abstract::P2Y(2) and P2Y(4) receptors are G protein-coupled receptors, activated by UTP and dinucleoside tetraphosphates, which are difficult to distinguish pharmacologically for lack of potent and selective ligands. We structurally varied phosphate and uracil moieties in analogues of pyrimidine nucleoside 5'-triphosphates and ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm101591j
更新日期:2011-06-23 00:00:00
abstract::5-(Ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole (ezutromid, 1) is a first-in-class utrophin modulator that has been evaluated in a phase 2 clinical study for the treatment of Duchenne muscular dystrophy (DMD). Ezutromid was found to undergo hepatic oxidation of its 2-naphthyl substituent to produce two regioisome...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.9b01547
更新日期:2020-03-12 00:00:00
abstract::2-Hydroxy-5-(3,4-dichlorophenyl)-6,7-bis(hydroxymethyl)-2,3-dihydro-1H- pyrrolizine bis(2-propylcarbamate) (11) was prepared in a multistep synthesis. The 2-hydroxy group was used to prepare ester prodrugs 14 and 15, and the antineoplastic activities of 11, 14, and 15a were compared to 1 (the 2-deoxy analogue of 11) i...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00363a023
更新日期:1983-09-01 00:00:00
abstract::6,6,8-Triethyldesmosdumotin B (2) was discovered as a MDR-selective flavonoid with significant in vitro anticancer activity against a multidrug resistant (MDR) cell line (KB-VIN) but without activity against the parent cells (KB). Additional 2 analogues were synthesized and evaluated to determine the effect of B-ring ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm100846r
更新日期:2010-09-23 00:00:00
abstract::Polynuclear Pt(II) complexes are a novel class of promising anticancer agents with potential clinical significance. A series of pyrazine (pz) bridged dinuclear Pt(II) complexes with general formulas {[Pt(L)Cl]2(μ-pz)}(2+) (L, ethylenediamine, en; (±)-1,2-propylenediamine, 1,2-pn; isobutylenediamine, ibn; trans-(±)-1,2...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm5017686
更新日期:2015-02-12 00:00:00
abstract::The proposed sst(1) pharmacophore (J. Med. Chem. 2005, 48, 523-533) derived from the NMR structures of a family of mono- and dicyclic undecamers was used to design octa-, hepta-, and hexamers with high affinity and selectivity for the somatostatin sst(1) receptor. These compounds were tested for their in vitro binding...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm801314f
更新日期:2009-05-14 00:00:00