Journal of medicinal chemistry
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A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), by specific targeting of the JAK1 pathway. Examination of the preferred binding conformation of clinically effective, pan-JAK inhibitor 1 led to identification of a novel, tricyclic hinge binding scaffold 3. ⋯ This study culminated in the identification of subnanomolar JAK1 inhibitors such as 22 and 49, having excellent cell potency, good rat pharmacokinetic characteristics, and excellent kinase selectivity. Determination of the binding modes of the series in JAK1 and JAK2 by X-ray crystallography supported the design of analogues to enhance affinity and selectivity.
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(N)-Methanocarba adenosine 5'-methyluronamides containing known A(3) AR (adenosine receptor)-enhancing modifications, i.e., 2-(arylethynyl)adenine and N(6)-methyl or N(6)-(3-substituted-benzyl), were nanomolar full agonists of human (h) A(3)AR and highly selective (K(i) ∼0.6 nM, N(6)-methyl 2-(halophenylethynyl) analogues 13 and 14). Combined 2-arylethynyl-N(6)-3-chlorobenzyl substitutions preserved A(3)AR affinity/selectivity in the (N)-methanocarba series (e.g., 3,4-difluoro full agonist MRS5698 31, K(i) 3 nM, human and mouse A(3)) better than that for ribosides. ⋯ The vicinity of receptor-bound C2 groups was probed by homology modeling based on recent X-ray structure of an agonist-bound A(2A)AR, with a predicted helical rearrangement requiring an agonist-specific outward displacement of TM2 resembling opsin. Thus, the X-ray structure of related A(2A)AR is useful in guiding the design of new A(3)AR agonists.
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The β-lactone ring of N-(2-oxo-3-oxetanyl)amides, a class of N-acylethanolamine acid amidase (NAAA) inhibitors endowed with anti-inflammatory properties, is responsible for both NAAA inhibition and low compound stability. Here, we investigate the structure-activity and structure-property relationships for a set of known and new β-lactone derivatives, focusing on the new class of N-(2-oxo-3-oxetanyl)carbamates. ⋯ A tert-butyl substituent in the side chain reduced the reactivity with bovine serum albumin. (2S,3R)-2-Methyl-4-oxo-3-oxetanylcarbamic acid 5-phenylpentyl ester (27, URB913/ARN077) inhibited NAAA with good in vitro potency (IC(50) = 127 nM) and showed improved stability. It is rapidly cleaved in plasma, which supports its use for topical applications.
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Structure-based design of a series of cyclic hydroxyethylamine BACE1 inhibitors allowed the rational incorporation of prime- and nonprime-side fragments to a central core template without any amide functionality. The core scaffold selection and the structure-activity relationship development were supported by molecular modeling studies and by X-ray analysis of BACE1 complexes with various ligands to expedite the optimization of the series. ⋯ Guided by structure-based optimization, we were able to obtain highly potent compounds such as 60p with enzymatic and cellular IC(50) values of 2 and 50 nM, respectively, and with >200-fold selectivity over cathepsin D. Pharmacodynamic studies in APP51/16 transgenic mice at oral doses of 180 μmol/kg demonstrated significant reduction of brain Aβ levels.
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Mycobacterial transcriptional repressor EthR controls the expression of EthA, the bacterial monooxygenase activating ethionamide, and is thus largely responsible for the low sensitivity of the human pathogen Mycobacterium tuberculosis to this antibiotic. We recently reported structure-activity relationships of a series of 1,2,4-oxadiazole EthR inhibitors leading to the discovery of potent ethionamide boosters. ⋯ This work was done using a combination of structure-based drug design and in vitro/ex vivo evaluations of ethionamide boosters on the targeted protein EthR and on the human pathogen Mycobacterium tuberculosis. Thanks to this process, we identified compound 42 (BDM41906), which displays improved efficacy in addition to high exposure to mice after oral administration.