This study reports the identification and Hits to Leads optimization of inhibitors of coactivator associated arginine methyltransferase (CARM1). Compound
7b is a potent, selective inhibitor of CARM1.
...This study reports the identification and Hits to Leads optimization of inhibitors of coactivator associated arginine methyltransferase (CARM1). Compound
7b is a potent, selective inhibitor of CARM1.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Design, synthesis, and SAR development led to the identification of the potent, novel, and selective pyrazole based inhibitor (7f) of CARM1.
Design, synthesis, and SAR development led to the ...identification of the potent, novel, and selective pyrazole based inhibitor (7f) of Coactivator Associated Arginine Methyltransferase (CARM1).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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Computer aided drug design led to a new class of spiro-barbiturates (e.g.,
4a, MMP-13
K
i
=
4.7
nM) that are potent inhibitors of MMP-13.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The design, synthesis, and SAR studies of ‘core’ variations led to identification of novel, selective, and potent small molecule antagonist (
22) of the CC chemokine receptor-4 (CCR4) with improved ...in vitro activity and liability profile. Compound
22 was efficacious in a murine allergic inflammation model (ED
50 10
mg/kg).
The design, synthesis, and SAR studies of ‘core’ variations led to identification of novel, selective, and potent small molecule antagonist (
22) of the CC chemokine receptor-4 (CCR4) with improved in vitro activity and liability profile. Compound
22 was efficacious in a murine allergic inflammation model (ED
50
∼
10
mg/kg).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
In a high-throughput screening effort, a series of tetrahydroisoquinolines was identified as modest inhibitors of human Eg5. A medicinal chemistry optimization effort led to the identification of
...R-4-(3-hydroxyphenyl)-
N,
N-7,8-tetramethyl-3,4-dihydroisoquinoline-2(1
H)-carboxamide (
32a) as a potent inhibitor of human Eg5 (ATPase IC
50 104
nM) with good anti-proliferative activity in A2780 cells (IC
50 234
nM).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Inhibition of the bromodomain and extra-terminal (BET) family of adaptor proteins is an attractive strategy for targeting transcriptional regulation of key oncogenes, such as c-MYC. Starting with the ...screening hit 1, a combination of structure–activity relationship and protein structure-guided drug design led to the discovery of a differently oriented carbazole 9 with favorable binding to the tryptophan, proline, and phenylalanine (WPF) shelf conserved in the BET family. Identification of an additional lipophilic pocket and functional group optimization to optimize pharmacokinetic (PK) properties culminated in the discovery of 18 (BMS-986158) with excellent potency in binding and functional assays. On the basis of its favorable PK profile and robust in vivo activity in a panel of hematologic and solid tumor models, BMS-986158 was selected as a candidate for clinical evaluation.
A novel series of histamine H3 receptor antagonists based on the 4-(1H-imidazol-4-yl)methylpiperidine template displaying low CYP2D6 and CYP3A4 inhibitory profiles has been identified. Structural ...features responsible for the reduction of P450 activity, a typical liability of 4-substituted imidazoles, have been established.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We report the discovery of novel histamine H(3) receptor antagonists based on 4-(1H-imidazol-4-yl)methylpiperidine. The most potent compounds in the series (e.g., 7) result from the attachment of a ...substituted aniline amide to the main pharmacophore piperidine via a two-methylene linker.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A kinome-wide selectivity screen of >20000 compounds with a rich representation of many structural classes has been completed. Analysis of the selectivity patterns for each class shows that a broad ...spectrum of structural scaffolds can achieve specificity for many kinase families. Kinase selectivity and potency are inversely correlated, a trend that is also found in a large set of kinase functional data. Although selective and nonselective compounds are mostly similar in their physicochemical characteristics, we identify specific features that are present more frequently in compounds that bind to many kinases. Our results support a scaffold-oriented approach for building compound collections to screen kinase targets.
