Structure-based design, SAR analysis and antitumor activity of PI3K/mTOR dual inhibitors from 4-methylpyridopyrimidinone series.

PI3K, AKT and mTOR, key kinases from a frequently dysregulated PI3K signaling pathway, have been extensively pursued to treat a variety of cancers in oncology. Clinical trials of PF-04691502, a highly potent and selective ATP competitive kinase inhibitor of class 1 PI3Ks and mTOR, from 4-methylpyridopyrimidinone series, led to the discovery of a metabolite with a terminal carboxylic acid, PF-06465603. This paper discusses structure-based drug design, SAR and antitumor activity of the MPP derivatives with a terminal alcohol, a carboxylic acid or a carboxyl amide.

N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11ß-hydroxysteroid dehydrogenase type 1: strategies to eliminate reactive metabolites.

N-(Pyridin-2-yl) arylsulfonamides 1 and 2 (PF-915275) were identified as potent inhibitors of 11ß-hydroxysteroid dehydrogenase type 1. A screen for bioactivation revealed that these compounds formed glutathione conjugates. This communication presents the results of a risk benefit analysis carried out to progress 2 (PF-915275) to a clinical study and the strategies used to eliminate reactive metabolites in this series of inhibitors. Based on the proposed mechanism of bioactivation and structure-activity relationships, design efforts led to N-(pyridin-2-yl) arylsulfonamides such as 18 and 20 that maintained potent 11ß-hydroxysteroid dehydrogenase type 1 activity, showed exquisite pharmacokinetic profiles, and were negative in the reactive metabolite assay.

4-methylpteridinones as orally active and selective PI3K/mTOR dual inhibitors.

Pteridinones were designed based on a non-selective kinase template. Because of the uniqueness of the PI3K and mTOR binding pockets, a methyl group was introduced to C-4 position of the peteridinone core to give compounds with excellent selectivity for PI3K and mTOR. This series of compounds were further optimized to improve their potency against PI3Kα and mTOR. Finally, orally active compounds with improved solubility and robust in vivo efficacy in tumor growth inhibition were identified as well.

trans-4-(2-Amino-5-bromo-6-methyl-pyrimidin-4-ylamino)-1-methyl-cyclo-hexa-nol.

The title compound, C(12)H(19)BrN(4)O, represents the minor component of the two products obtained in a series of transformations involving the Grignard reaction of tert-butoxy-carbonyl-protected 4-amino-cyclo-hexa-none with MeMgBr, and subsequent inter-action of the obtained amino-substituted cyclo-hexa-nol with 4-chloro-6-methyl-pyrimidin-2-amine followed by bromination with N-bromo-succinimide. The X-ray structure showed that this product represents a trans isomer with respect to the amino and hydr-oxy substituents in the cyclo-hexyl ring; the dihedral angle between the amino-pyrimidine plane and the (noncrystallographic) mirror plane of the substituted cyclo-hexyl fragment is 33.6 (3)°. Only two of the four potentially 'active' H atoms participate in inter-molecular N-H⋯O and O-H⋯N hydrogen bonds, linking the mol-ecules into layers parallel to the (10) plane.