Bruton's tyrosine kinase (BTK), a member of the TEC family of kinases, plays a crucial role in B-cell maturation and mast cell activation. Although the structures of the unphosphorylated mouse BTK kinase domain and the unphosphorylated and phosphorylated kinase domains of human ITK are known, understanding the kinase selectivity profiles of BTK inhibitors has been hampered by the lack of availability of a high resolution, ligand-bound BTK structure. Here, we report the crystal structures of the human BTK kinase domain bound to either Dasatinib (BMS-354825) at 1.9 Å resolution or to 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolospyrimidin-7-yl-cyclopentane at 1.6 Å resolution. This data provides information relevant to the development of small molecule inhibitors targeting BTK and the TEC family of nonreceptor tyrosine kinases. Analysis of the structural differences between the TEC and Src families of kinases near the Trp-Glu-Ile motif in the N-terminal region of the kinase domain suggests a mechanism of regulation of the TEC family members.
Neuropeptide Y (NPY) has been shown to play an important role in the regulation of food intake and energy balance. Pharmacological data suggests that the Y5 receptor subtype contributes to the effects of NPY on appetite, and therefore a Y5 antagonist might be a useful therapeutic agent for the treatment of obesity. In attempts to identify potential Y5 antagonists, a series of pyrrolo[3, 2-d]pyrimidine derivatives was prepared and evaluated for their ability to bind to Y5 receptors in vitro. We report here the synthesis and initial structure-activity relationship investigations for this class of compounds. The target compounds were prepared by a variety of synthetic routes designed to modify both the substitution and the heterocyclic core of the pyrrolo[3,2-d]pyrimidine lead 1. In addition to identifying several potent Y5 antagonists for evaluation as potential antiobesity agents, a pharmacophore model for the human Y5 receptor is presented.
The synthesis of
9,9-difluoro-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one
(F2CBI), a difluorocyclopropane analog of the CC-1065 and duocarmycin alkylation subunits
which represents the first such agent containing
substitution of the reactive center in the natural products, is
detailed. The core structure of F2CBI was
prepared by
an intramolecular metal carbenoid insertion reaction into a
1,1-difluoroalkene (74%) employing a
p-quinonediazide,
and its incorporation into F2CBI-TMI (24)
provided a key analog of the duocarmycins. A study of the
solvolysis of
N-BOC-F2CBI (19) revealed that
introduction of the difluorocyclopropane substitution increased the
reactivity 500×
without altering the inherent regioselectivity which occurred with
nucleophilic addition to the difluoro substituted
C9 cyclopropane carbon. A single-crystal X-ray structure analysis
of 17 and its comparison with the X-ray
structures
of CBI and related agents beautifully reveal the structural origin of
the difluoro substitution effects on the reactivity
and regioselectivity of the cyclopropane cleavage reaction. The
cyclopropane C−CF2−C bond angle is
expanded,
and the carbon−carbon bond opposite the difluoro substitution is
lengthened to accommodate the preferentially
compressed exocyclic F−C−F bond angle introducing additional strain
energy. Consistent with this increased reactivity
and following trends established to date, the agents were found to be
500−1000× less cytotoxic than the corresponding
CBI derivative lacking the difluorocyclopropane substitution.
Similarly, the gem difluoro substitution had no
perceptible effect on the DNA alkylation selectivity of the agents, and
they were found to undergo the characteristic
adenine N3 addition to the C9 cyclopropane carbon but did so with a
reduced (675−725×) efficiency following the
cytotoxicity and stability correlations.
BF 3 ‚Et 2 O-catalyzed geminal acylation of ketones and acetals with 3-methyl-1,2-bis[(trimethylsilyl)oxy)]cyclobutene (3) provided methylcyclopentanediones in yields that ranged from 40 to 94%. The best substrates were unhindered cyclohexanones. With acetals, stereochemical preferences in the initial Mukaiyama-like aldol step giving cyclobutanones translated into the stereochemistry of the ultimate cyclopentanedione products. With ketones, equilibration of the initial cyclobutanone compounds resulted in cyclopentanedione products with a different stereochemical preference. The gem-dimethylcyclobutene reagent 4 reacted with ketones to give gem-dimethylcyclopentanediones in modest yield. The process was much more stereochemically efficient than the reaction with 3. Rearrangement from the initial cyclobutanone compound was partially diverted toward air-sensitive 3-furanone compounds and ring-opened 1,2-diones. Only furanones (e.g., 52 and 53) were isolated from reactions with the tetramethylcyclobutene 51.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.