Technically Extended MultiParameter Optimization (TEMPO): An Advanced Robust Scoring Scheme To Calculate Central Nervous System Druggability and Monitor Lead Optimization

At the discovery stage, it is important to understand the drug design concepts for a CNS drug compared to those for a non-CNS drug. Previously, we published on ideal CNS drug property space and defined in detail the physicochemical property distribution of CNS versus non-CNS oral drugs, the application of radar charting (a graphical representation of multiple physicochemical properties used during CNS lead optimization), and a recursive partition classification tree to differentiate between CNS- and non-CNS drugs. The objective of the present study was to further understand the differentiation of physicochemical properties between CNS and non-CNS oral drugs by the development and application of a new CNS scoring scheme: Technically Extended MultiParameter Optimization (TEMPO). In this multiparameter method, we identified eight key physicochemical properties critical for accurately assessing CNS druggability: (1) number of basic amines, (2) carbon–heteroatom (non-carbon, non-hydrogen) ratio, (3) number of aromatic rings, (4) number of chains, (5) number of rotatable bonds, (6) number of H-acceptors, (7) computed octanol/water partition coefficient (AlogP), and (8) number of nonconjugated C atoms in nonaromatic rings. Significant features of the CNS-TEMPO penalty score are the extension of the multiparameter approach to generate an accurate weight factor for each physicochemical property, the use of limits on both sides of the computed property space range during the penalty calculation, and the classification of CNS and non-CNS drug scores. CNS-TEMPO significantly outperformed CNS-MPO and the Schrödinger QikProp CNS parameter (QP_CNS) in evaluating CNS drugs and has been extensively applied in support of CNS lead optimization programs

Discovery of an Orally Efficacious Inhibitor of Anaplastic Lymphoma Kinase

Anaplastic lymphoma kinase (ALK) is a promising therapeutic target for the treatment of cancer, supported by considerable favorable preclinical and clinical activities over the past several years and culminating in the recent FDA approval of the ALK inhibitor crizotinib. Through a series of targeted modifications on an ALK inhibitor diaminopyrimidine scaffold, our research group has driven improvements in ALK potency, kinase selectivity, and overall pharmaceutical properties. Optimization of this scaffold has led to the identification of a potent and efficacious inhibitor of ALK, <b>25b</b>. A striking feature of <b>25b</b> over previously described ALK inhibitors is its >600-fold selectivity over insulin receptor (IR), a closely related kinase family member. Most importantly, <b>25b</b> exhibited dose proportional escalation in rat compared to compound <b>3</b> which suffered dose limiting absorption preventing further advancement. Compound <b>25b</b> exhibited significant in vivo antitumor efficacy when dosed orally in an ALK-positive ALCL tumor xenograft model in SCID mice, warranting further assessment in advanced preclinical models

Strategies to Mitigate the Bioactivation of 2-Anilino-7-Aryl-Pyrrolo[2,1-<i>f</i>][1,2,4]triazines: Identification of Orally Bioavailable, Efficacious ALK Inhibitors

Chemical strategies to mitigate cytochrome P450-mediated bioactivation of novel 2,7-disubstituted pyrrolo­[2,1-<i>f</i>]­[1,2,4]­triazine ALK inhibitors are described along with synthesis and biological activity. Piperidine-derived analogues showing minimal microsomal reactive metabolite formation were discovered. Potent, selective, and metabolically stable ALK inhibitors from this class were identified, and an orally bioavailable compound (<b>32</b>) with antitumor efficacy in ALK-driven xenografts in mouse models was extensively characterized

Discovery of Clinical Candidate CEP-37440, a Selective Inhibitor of Focal Adhesion Kinase (FAK) and Anaplastic Lymphoma Kinase (ALK)

Analogues structurally related to anaplastic lymphoma kinase (ALK) inhibitor <b>1</b> 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 <b>27b</b>, including details surrounding SAR, in vitro/in vivo pharmacology, and pharmacokinetics, is reported herein