Discovery of AZD6642, an Inhibitor of 5-Lipoxygenase Activating Protein (FLAP) for the Treatment of Inflammatory Diseases

Abstract

A drug discovery program in search of novel 5-lipoxygenase activating protein (FLAP) inhibitors focused on driving a reduction in lipophilicity with maintained or increased ligand lipophilic efficiency (LLE) compared to previously reported compounds led to the discovery of AZD6642 (15b). Introduction of a hydrophilic tetrahydrofuran (THF) ring at the stereogenic central carbon atom led to a significant shift in physicochemical property space. The structure-activity relationship exploration and optimization of DMPK properties leading to this compound are described in addition to pharmacokinetic analysis and an investigation of the pharmacokinetic (PK)-pharmacodynamic (PD) relationship based on ex vivo leukotriene B4 (LTB4) levels in dog. AZD6642 shows high specific potency and low lipophilicity, resulting in a selective and metabolically stable profile. On the basis of initial PK/PD relation measured, a low dose to human was predicted.

In silico ADME in drug design – enhancing the impact

“…Data set 1 was a set of 27 drug discovery compounds exemplifying important compounds leading towards candidate selection [11]. Data set 2 was a set of 21 marketed drugs, for which potency data, dosing information and human pharmacokinetic data had been collated and used to show feasibility of early D2M predictions [9].…”

“…As proof of concept a set of drug discovery molecules leading towards a candidate structure [11] was evaluated. Intrinsic clearance in human hepatocytes, fraction unbound in the incubation, fraction unbound in plasma, volume of distribution and intrinsic Caco2 permeability were predicted for all compounds using the present in-house models (see Table 1) and minimum and maximum plasma concentrations for a once daily oral dose of 100 mg calculated using equations 2 and 3.…”

“…By reverting the D2M equation and setting the target dose to, for example, 100 mg once daily, the achievable plasma concentration can be calculated from in silico predicted parameters and the minimum required potency ("threshold pIC50") defined as ranking score for virtual compounds. We show how such a ranking score could be used in the discovery setting on the example of a set of 27 compounds leading towards a candidate structure [11]. We also test the concept on a set of known drugs with information about dosing and human pharmacokinetics [9] and compare the results from purely in silico predictions to those from in vitro data and from human in vivo data.…”

A Single Amino Acid Difference between Mouse and Human 5-Lipoxygenase Activating Protein (FLAP) Explains the Speciation and Differential Pharmacology of Novel FLAP Inhibitors

“…Its function is to present arachidonic acid to 5-lipoxygenase for conversion to leukotriene A 4 and subsequently present leukotriene A 4 to leukotriene C 4 synthase to generate the potent pro-inflammatory mediator leukotriene C 4 (2)(3)(4). Because of this critical role in the biosynthesis of leukotrienes, FLAP has been the subject of multiple drug discovery efforts (5,6), with several inhibitors reaching proof of concept in small clinical trials (7)(8)(9).…”

Synthesis of [3H] and [2H6]AZD6642, an inhibitor of 5‐lipoxygenase activating protein (FLAP)

“…FLAP is required for the initial conversion of AA to 5‐hydroperoxyeicosatetraenoic acid; therefore, inhibitors of FLAP should block the production of leukotrienes . An AstraZeneca effort to identify a FLAP inhibitor with good drug properties resulted in the identification of AZD6642 ( 1 ) and compound 2 (Figure ) …”