High-affinity, functionally potent, urea-based antagonists of CCR1 have been discovered. Modulation of PXR transactivation has revealed the selective and orally bioavailable CCR1 antagonist ...BMS-817399 (29), which entered clinical trials for the treatment of rheumatoid arthritis.
We encountered a dilemma in the course of studying a series of antagonists of the G-protein coupled receptor CC chemokine receptor-2 (CCR2): compounds with polar C3 side chains exhibited good ion ...channel selectivity but poor oral bioavailability, whereas compounds with lipophilic C3 side chains exhibited good oral bioavailability in preclinical species but poor ion channel selectivity. Attempts to solve this through the direct modulation of physicochemical properties failed. However, the installation of a protonation-dependent conformational switching mechanism resolved the problem because it enabled a highly selective and relatively polar molecule to access a small population of a conformer with lower polar surface area and higher membrane permeability. Optimization of the overall properties in this series yielded the CCR2 antagonist BMS-741672 (7), which embodied properties suitable for study in human clinical trials.
A series of compounds which exhibited good human CCR1 binding and functional potency was modified resulting in the discovery of a novel series of high affinity, functionally potent antagonists of the ...CCR1 receptor. Issues of PXR activity, ion-channel potency, and poor metabolic stability were addressed by the addition of a hydroxyl group to an otherwise lipophilic area in the molecule resulting in the discovery of preclinical candidate BMS-457 for the treatment of rheumatoid arthritis.
We report the synthesis of 3-phenylsulfonylmethyl cyclohexylaminobenzamides (4) as CCR2 inhibitors for the potential treatment of inflammatory diseases. Several of the compounds display nanomolar ...binding affinity for CCR2. The in vitro structure–activity relationships of 4 are described, and are also reconciled with those from the related 2-phenylsulfonylmethyl series.
We report the synthesis of 3-phenylsulfonylmethyl cyclohexylaminobenzamides (4) as CCR2 inhibitors for the potential treatment of inflammatory diseases. Several of the compounds display nanomolar binding affinity for CCR2. The in vitro structure–activity relationships of 4 are described, and are also reconciled with those from the related 2-phenylsulfonylmethyl series.
To improve the metabolic stability profile of BMS-741672 (1a), we undertook a structure–activity relationship study in our trisubstituted cyclohexylamine series. This ultimately led to the ...identification of 2d (BMS-753426) as a potent and orally bioavailable antagonist of CCR2. Compared to previous clinical candidate 1a, the tert-butyl amine 2d showed significant improvements in pharmacokinetic properties, with lower clearance and higher oral bioavailability. Furthermore, compound 2d exhibited improved affinity for CCR5 and good activity in models of both monocyte migration and multiple sclerosis in the hCCR2 knock-in mouse. The synthesis of 2d was facilitated by the development of a simplified approach to key intermediate (4R)-9b that deployed a stereoselective reductive amination which may prove to be of general interest.
Prodrugs that exhibit ex vivo instability owing to high levels of esterases in rodent blood, plasma and serum present challenges in the accurate determination of drug exposure in samples from ...pharmacokinetic, pharmacokinetic/pharmacodynamic, efficacy and toxicology studies in drug discovery. Ensuring the stability of analytes in sample collection, handling, analysis and storage must be established for program progression. Current protocols for the stabilization of prodrugs include the immediate quenching of whole blood with acetonitrile or methanol to stop enzyme activity, or the addition of an esterase inhibitor such as phenylmethanesulfonyl fluoride to the blood collection tubes before serum or plasma is generated. Dried blood spots (DBS) sampling may offer an alternative prodrug stabilization method for sample collection and storage from rodent studies in drug discovery.
Two different prodrugs of the same parent compound that were known to exhibit ex vivo instability in rodent blood were selected for the evaluation of DBS for analyte stabilization. Each prodrug was spiked separately into fresh rat EDTA whole blood and prepared three ways: from liquid whole blood, prepared and analyzed as lysate; from whole blood spotted onto Whatman 903(®) Protein Saver untreated cards (903 cards); and from whole blood spotted onto Whatman FTA(®) Elute Micro treated cards, currently known as DMPK-B cards (FTA cards). Samples were extracted by filtration-assisted protein precipitation at 0, 2, 5 and 24 h and 4, 7, 14 and 21 days after spiking and analyzed by UHPLC-MS/MS.
For these two prodrugs, stability on DBS cards was observed in rat EDTA whole blood for at least 21 days at room temperature as determined by loss of prodrug and appearance of parent. The Whatman FTA Elute cards, treated with reagents that lyse cells, did not offer more stability for the investigated compounds than the Whatman 903 Protein Saver untreated cards.
We describe the hybridization of our previously reported acyclic and cyclic CC chemokine receptor 2 (CCR2) antagonists to lead to a new series of dual antagonists of CCR2 and CCR5. Installation of a ...γ-lactam as the spacer group and a quinazoline as a benzamide mimetic improved oral bioavailability markedly. These efforts led to the identification of 13d, a potent and orally bioavailable dual antagonist suitable for use in both murine and monkey models of inflammation.
Starting with our previously described(20) class of CC chemokine receptor-3 (CCR3) antagonist, we improved the potency by replacing the phenyl linker of 1 with a cyclohexyl linker and by replacing ...the 4-benzylpiperidine with a 3-benzylpiperidine. The resulting compound, 32, is a potent and selective antagonist of CCR3. SAR studies showed that the 3-acetylphenyl urea of 32 could be replaced with heterocyclic ureas or heterocyclic-substituted phenyl ureas and still maintain the potency (inhibition of eotaxin-induced chemotaxis) of this class of compounds in the low-picomolar range (IC(50) = 10-60 pM), representing some of the most potent CCR3 antagonists reported to date. The potency of 32 for mouse CCR3 (chemotaxis IC(50) = 41 nM) and its oral bioavailability in mice (20% F ) were adequate to assess the efficacy in animal models of allergic airway inflammation. Oral administration of 32 reduced eosinophil recruitment into the lungs in a dose-dependent manner in these animal models. On the basis of its overall potency, selectivity, efficacy, and safety profile, the benzenesulfonate salt of 32, designated DPC168, entered phase I clinical trials.
We describe the design, synthesis, and evaluation, of γ-lactams as glycinamide replacements within a series of di- and trisubstituted cyclohexane CCR2 antagonists.
We describe the design, synthesis, ...and evaluation, of γ-lactams as glycinamide replacements within a series of di- and trisubstituted cyclohexane CCR2 antagonists. The lactam-containing trisubstituted cyclohexanes proved to be more potent than the disubstituted analogs, as trisubstituted analog, lactam
13, displayed excellent activity (CCR2 binding IC
50
=
1.0
nM and chemotaxis IC
50
=
0.5
nM) and improved metabolic stability over its parent glycinamide.
Conformational analysis of
trans-1,2-disubstituted cyclohexane CCR3 antagonist
2 revealed that the cyclohexane linker could be replaced by an acyclic
syn-α-methyl-β-hydroxypropyl linker. It was found ...that the α-methyl group lowered protein binding and the β-hydroxyl group lowered affinity for CYP2D6. Urea
31 (BMS-639623) with a chemotaxis IC
50
=
38
pM for eosinophils was chosen to enter clinical development.
Conformational analysis of
trans-1,2-disubstituted cyclohexane CCR3 antagonist
2 revealed that the cyclohexane linker could be replaced by an acyclic
syn-α-methyl-β-hydroxypropyl linker. Synthesis and biological evaluation of mono- and disubstituted propyl linkers support this conformational correlation. It was also found that the α-methyl group to the urea lowered protein binding and that the β-hydroxyl group lowered affinity for CYP2D6. Ab initio calculations show that the α-methyl group governs the spatial orientation of three key functionalities within the molecule. α-Methyl-β-hydroxypropyl urea
31 with a chemotaxis IC
50
=
38
pM for eosinophils was chosen to enter clinical development for the treatment of asthma.
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