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Discovery of AZD3147: a potent, selective dual inhibitor of mTORC1 and mTORC2.

Journal of medicinal chemistry (2015-02-03)
Kurt G Pike, Jeff Morris, Linette Ruston, Sarah L Pass, Ryan Greenwood, Emma J Williams, Julie Demeritt, Janet D Culshaw, Kristy Gill, Martin Pass, M Raymond V Finlay, Catherine J Good, Craig A Roberts, Gordon S Currie, Kevin Blades, Jonathan M Eden, Stuart E Pearson
ABSTRACT

High throughput screening followed by a lead generation campaign uncovered a novel series of urea containing morpholinopyrimidine compounds which act as potent and selective dual inhibitors of mTORC1 and mTORC2. We describe the continued compound optimization campaign for this series, in particular focused on identifying compounds with improved cellular potency, improved aqueous solubility, and good stability in human hepatocyte incubations. Knowledge from empirical SAR investigations was combined with an understanding of the molecular interactions in the crystal lattice to improve both cellular potency and solubility, and the composite parameters of LLE and pIC50-pSolubility were used to assess compound quality and progress. Predictive models were employed to efficiently mine the attractive chemical space identified resulting in the discovery of 42 (AZD3147), an extremely potent and selective dual inhibitor of mTORC1 and mTORC2 with physicochemical and pharmacokinetic properties suitable for development as a potential clinical candidate.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Ammonium hydroxide solution, ACS reagent, 28.0-30.0% NH3 basis
Sigma-Aldrich
Formic acid, reagent grade, ≥95%
Sigma-Aldrich
Ammonium hydroxide solution, 28% NH3 in H2O, ≥99.99% trace metals basis
Sigma-Aldrich
Formic acid, puriss. p.a., ACS reagent, reag. Ph. Eur., ≥98%
Sigma-Aldrich
Formic acid, ACS reagent, ≥96%
Sigma-Aldrich
Formic acid, puriss., meets analytical specifications of DAC, FCC, 98.0-100%
Sigma-Aldrich
Ammonium hydroxide solution, puriss., 30-33% NH3 in H2O
Sigma-Aldrich
Formic acid, ACS reagent, ≥88%
Sigma-Aldrich
Ammonium hydroxide solution, BioUltra, ~1 M NH3 in H2O (T)
Sigma-Aldrich
Ammonium hydroxide solution, puriss. p.a., reag. ISO, reag. Ph. Eur., ~25% NH3 basis
Sigma-Aldrich
Formic acid, ≥95%, FCC, FG
Sigma-Aldrich
Ammonium hydroxide solution, puriss., meets analytical specification of Ph. Eur., 25-30% NH3 basis
Sigma-Aldrich
Formic acid solution, BioUltra, 1.0 M in H2O
Sigma-Aldrich
Ammonium hydroxide solution, puriss. p.a. plus, ≥25% NH3 in H2O