This paper describes the identification and optimization of a novel series of DFG-out binding p38 inhibitors as inhaled agents for the treatment of chronic obstructive pulmonary disease. Structure based drug design and "inhalation by design" principles have been applied to the optimization of the lead series exemplied by compound 1a. Analogues have been designed to be potent and selective for p38, with an emphasis on slow enzyme dissociation kinetics to deliver prolonged lung p38 inhibition. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimize systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance and glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimize drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity, and solubility were considered to ensure compatibility with a dry powder inhaler. 1ab (PF-03715455) was subsequently identified as a clinical candidate from this series with efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of COPD.
There
is an urgent need for new treatments for visceral leishmaniasis
(VL), a parasitic infection which impacts heavily large areas of East
Africa, Asia, and South America. We previously reported on the discovery
of GSK3494245/DDD01305143 (
1
) as a preclinical candidate
for VL and, herein, we report on the medicinal chemistry program that
led to its identification. A hit from a phenotypic screen was optimized
to give a compound with
in vivo
efficacy, which was
hampered by poor solubility and genotoxicity. The work on the original
scaffold failed to lead to developable compounds, so an extensive
scaffold-hopping exercise involving medicinal chemistry design,
in silico
profiling, and subsequent synthesis was utilized,
leading to the preclinical candidate. The compound was shown to act
via proteasome inhibition, and we report on the modeling of different
scaffolds into a cryo-EM structure and the impact this has on our
understanding of the series’ structure–activity relationships.
A well-documented obstacle in the synthesis of functionalized rhodamine dyes is the generation of regioisomers which are difficult to separate. These isomers occur due to the use of unsymmetrical anhydride reagents, which possess two potential points of reactivity where condensation with meta-aminophenols can take place. In this report we describe a method which eliminates this problem by using phthalaldehydic acids as anhydride replacements. These reagents provide only one point of reactivity for the aminophenol, thus allowing direct access to single isomer tetramethylrhodamines and avoiding isomer generation altogether. A range of functionalities are shown to be tolerated at the 5- and 6-position of the dye compounds which are prepared in up to gram quantities using our method. The scope of the method is further demonstrated by the preparation of additional rhodamine family members Rhodamine B and X-Rhodamine.
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