Screening of our chemical library using a rat corticotropin-releasing hormone (CRH) receptor assay led to the discovery that 2-anilinopyrimidine 15-1 weakly displaced [125I]-0-Tyr-oCRH from rat frontal cortex homogenates when compared to the known peptide antagonist alpha-helical CRH(9-41) (Ki = 5700 nM vs 1 nM). Furthermore, 15-1 weakly inhibited CRH-stimulated adenylate cyclase activity in the same tissue, but it was less potent than alpha-helical CRH(9-41) (IC50 = 20 000 nM vs 250 nM). Systematic structure-activity relationship studies, using the cloned human CRH1 receptor assay, defined the pharmacophore for optimal binding to hCRH1 receptors. Several high-affinity 2-anilinopyrimidines and -triazines were discovered, some of which had superior pharmacokinetic profiles in the rat. This paper describes the structure-activity studies which improved hCRH1 receptor binding affinity and pharmacokinetic parameters in the rat. Compound 28-17 (mean hCRH1 Ki = 32 nM) had a significantly improved pharmacokinetic profile in the rat (19% oral bioavailability at 30 mg/kg) as well as in the dog (20% oral bioavailability at 5 mg/kg) relative to the early lead structures.

Analogues structurally related to anaplastic lymphoma kinase (ALK) inhibitor 1 were optimized for metabolic stability. The results from this endeavor not only led to improved metabolic stability, pharmacokinetic parameters, and in vitro activity against clinically derived resistance mutations but also led to the incorporation of activity for focal adhesion kinase (FAK). FAK activation, via amplification and/or overexpression, is characteristic of multiple invasive solid tumors and metastasis. The discovery of the clinical stage, dual FAK/ALK inhibitor 27b, including details surrounding SAR, in vitro/in vivo pharmacology, and pharmacokinetics, is reported herein.

A series of novel 7-amino-1, 3,4,5-tetrahydrobenzo[b]azepin-2-one derivatives within the diaminopyrimidine class of kinase inhibitors were identified that target anaplastic lymphoma kinase (ALK). These inhibitors are potent against ALK in an isolated enzyme assay and inhibit autophosphorylation of the oncogenic fusion protein NPM-ALK in anaplastic large cell lymphoma (ALCL) cell lines. The lead inhibitor 15, which incorporates a bicyclo[2.2.1]hept-5-ene ring system in place of an aryl moiety, activates the pro-apoptotic caspases (3 and 7) and displays selective cytotoxicity against ALK-positive ALCL cells. Furthermore, 15 provides more than 40-fold selectivity against the structurally related insulin receptor, is orally bioavailable in multiple species, and displays in vivo antitumor efficacy when dosed orally in ALK-positive ALCL tumor xenografts in Scid mice.