Discovery and optimization of pyrazole amides as antagonists of CCR1

A HTS screen for CCR1 antagonists afforded a novel sub-micromolar hit 5 containing a pyrazole core. In this report the design, optimization, and SAR of novel CCR1 antagonists based on a pyrazole core motif is presented. Optimization led to the advanced candidate compounds (S)-16q and (S)-16r with 250-fold improved CCR1 potency, excellent off-target selectivity and attractive drug-like properties.     

Alpha-aminothiazole-gamma-aminobutanoic amides as potent, small molecule CCR2 receptor antagonists

A series of racemic and homochiral alpha-aminothiazole-gamma-aminobutyroamides that display high affinities for human and murine CCR2 and functional antagonism by inhibition of monocyte recruitment are described. A representative example is (2S)-2-[2-(acetylamino)-1,3-thiazol-4-yl]-N-[3-methyl-5-(trifluoromethyl)benzyl]-4-(4-phenylpiperidin-1-yl)butanamide, which shows 5 nM affinity for human monocytes and CHO cells expressing the human CCR2b receptor. It also inhibited MCP-1 initiated chemotaxis of human monocytes with an IC50 of 0.69 nM.     

3D-QSAR studies of substituted 1-(3, 3-diphenylpropyl)-piperidinyl amides and ureas as CCR5 receptor antagonists

3D-QSAR studies on the derivatives of 1-(3,3-diphenylpropyl)-piperidinyl amide and urea as CCR5 receptor antagonists were performed by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA) methods to rationalize the structural requirements responsible for the inhibitory activity of these compounds. The global minimum energy conformer of the template molecule, the most active and pharmacokinetically stable molecule of the series, was obtained by systematic search and used to build structures of the molecules in the dataset. The best predictions for the CCR5-receptor were obtained with the CoMFA standard model (q ² = 0.787, r ² = 0.962) and CoMSIA model combined steric, electrostatic and hydrophobic fields (q ² = 0.809, r ² = 0.951). The predictive ability of CoMFA and CoMSIA were determined using a test set of 12 compounds giving predictive correlation coefficients of 0.855 and 0.83, respectively, indicating good predictive power. Further, the robustness of the model was verified by bootstrapping analysis. The contour maps produced by the CoMFA and CoMSIA models were used to identify the structural features relevant to the biological activity in this series. Based on the CoMFA and CoMSIA analysis, we have identified some key features in the series that are responsible for CCR5 antagonistic activity which may be used to design more potent 1-(3,3-diphenylpropyl)-piperidinyl derivatives and predict their activity prior to synthesis. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Optimization of 2-aminothiazole derivatives as CCR4 antagonists

A series of 2-aminothiazole-derived antagonists of the CCR4 receptor has been synthesized and their affinity for the receptor evaluated using a [(125)I]TARC (CCL17) displacement assay. Optimization of these compounds for potency and pharmacokinetic properties led to the discovery of potent, orally bioavailable antagonists.     

Discovery and SAR of trisubstituted thiazolidinones as CCR4 antagonists

Substituted thiazolidinones were identified as CCR4 antagonists from high throughput screening. Subsequent lead optimization efforts resulted in defined structure-activity relationships and the identification of potent antagonists (compounds 90 and 91) that inhibited the chemotaxis of Th2 T-cells in vitro.     

Pyrrolidinyl phenylurea derivatives as novel CCR3 antagonists

Optimization starting with our lead compound 1 (IC₅₀ = 4.9 nM) led to the identification of pyrrolidinyl phenylurea derivatives. Further modification toward improvement of the bioavailability provided (R)-1-(1-((6-fluoronaphthalen-2-yl)methyl)pyrrolidin-3-yl)-3-(2-(2-hydroxyethoxy)phenyl)urea 32 (IC₅₀ = 1.7 nM), a potent and orally active CCR3 antagonist.     

Pyrazolone methylamino piperidine derivatives as novel CCR3 antagonists

The discovery and optimization of a novel class of potent CCR3 antagonists is described. Details of synthesis and SAR are given together with some ADME properties of selected compounds. An optimal balance between activities, physicochemical properties, and in vitro metabolic stability was reached by the proper choice of substituents.     

Novel 2-aminooctahydrocyclopentalene-3a-carboxamides as potent CCR2 antagonists

Novel CCR2 antagonists with a novel 2-aminooctahydrocyclopentalene-3a-carboxamide scaffold were designed. SAR studies led to a series of potent compounds. For example, compound 51 had a good PK profile in both dog and monkey, and exhibited excellent efficacy when dosed orally in an inflammation model in hCCR2 KI mice. In addition, an asymmetric synthesis to the core structures was developed.     

Discovery of novel aminothiadiazole amides as selective EP3 receptor antagonists

This Letter discloses a series of 2-aminothiadiazole amides as selective EP₃ receptor antagonists. SAR optimization resulted in compounds with excellent functional activity in vitro. In addition, efforts to optimize DMPK properties in the rat are discussed. These efforts have resulted in the identification of potent, selective EP₃ receptor antagonists with excellent DMPK properties suitable for in vivo studies.     

The synthesis of substituted bipiperidine amide compounds as CCR3 antagonists

Bipiperidine amide 1 has been identified as a CC chemokine receptor 3 (CCR3) antagonist. Optimization of its structure-activity relationship has resulted in the identification of cis (R,R)-4-[(3,4-dichlorophenyl)methyl]-3-hydroxymethyl-1'(6-quinolinylcarbonyl)-1,4'-bipiperidine 14n, which exhibits potent receptor affinity and inhibition of both calcium flux and eosinophil chemotaxis.     

Design and synthesis of novel CCR3 antagonists

As part of our investigation into the development of potent CCR3 antagonists, a series of piperidine analogues was designed and prepared. Exploration of the piperidine core examined both the basicity and the location of a nitrogen, as well as conformational variants. The bicyclo-piperidine 24c was found to be the most potent inhibitor of CCR3 with an IC(50) of 0.0082 microM in the binding assay and 0.0024 microM in the chemotaxis assay.     

Ligand-based design of GLUT inhibitors as potential antitumor agents

Glucose transporters (GLUTs) regulate glucose uptake and are often overexpressed in several human tumors. To identify new chemotypes targeting GLUT1, we built a pharmacophore model and searched against a NCI compound database. Sixteen hit molecules with good docking scores were screened for GLUT1 inhibition and antiproliferative activities. From these, we identified that compounds 2, 5, 6 and 13 inhibited the cell viability in a dose-dependent manner and that the IC₅₀s of 2 and 6 are<10 µM concentration in the HCT116 colon cancer cell line. Lead compound 13 (NSC295720) was a GLUT1 inhibitor. Docking studies show that GLUT1 residues Phe291, Phe379, Glu380, Trp388, and Trp412 were important for inhibitor binding.     

The design and discovery of novel amide CCR5 antagonists

The synthesis of a range of novel amine-containing structures and their primary potency as inhibitors of HIV-1 fusion via blocking of the CCR5 receptor is described. The development of the medicinal chemistry strategy and SAR’s which led to the identification of the piperidine amide compounds 33 and 36 as excellent leads for further evaluation is described, along with key physicochemical data which highlighted their lead potential.     

Discovery and SAR of 5-aminooctahydrocyclopentapyrrole-3a-carboxamides as potent CCR2 antagonists

SAR study of 5-aminooctahydrocyclopentapyrrole-3a-carboxamide scaffold led to identification of several CCR2 antagonists with potent activity in both binding and functional assays. Their cardiovascular safety and pharmacokinetic properties were also evaluated.     

N-Arylalkylpiperidine urea derivatives as CC chemokine receptor-3 (CCR3) antagonists

The synthesis and structure-activity relationships of N-arylalkylpiperidylmethyl ureas as antagonists of the CC chemokine receptor-3 (CCR3) are presented. These compounds displayed potent binding to the receptor as well as functional antagonism of eotaxin-elicited effects on eosinophils.     

Lead identification of benzimidazolone and azabenzimidazolone arylsulfonamides as CC-chemokine receptor 4 (CCR4) antagonists

A knowledge-based library of 2,3-dichlorophenylsulfonyl derivatives of commercially available aryl amines was synthesised and screened as human CCR4 antagonists, in order to identify a suitable hit for the start of a lead-optimisation programme. Hits were required to be more potent than an existing indazole series, have better physicochemical properties (c log P <3.5, chrom log D_7.4 <5.3 and CLND solubility >116 μg/mL), and be stable to acid and light. The benzimidazol-2-one core was identified as a hit suitable for further investigation. Substitution at N1 with small alkyl groups was tolerated; however, these analogues were inactive in the whole blood assay (pA₂ <5). Azabenzimidazolone analogues were all found to be active, with compound 38 exhibiting whole blood activity of 6.1, low molecular weight (389) and chrom log D_7.4 (2.4), high LE (0.43), and solubility (152 μg/mL). In addition, 38 had human serum albumin binding of around 93% and met all the criteria for progression to lead optimisation.     

Novel pyrrolidine heterocycles as CCR1 antagonists

A novel series of pyrrolidine heterocycles was prepared and found to show potent inhibitory activity of CCR1 binding and CCL3 mediated chemotaxis of a CCR1-expressing cell line. A potent, optimized triazole lead from this series was found to have acceptable pharmacokinetics and microsomal stability in rat and is suitable for further optimization and development.     

Oxazolidinones as novel human CCR8 antagonists

High-throughput screening of the corporate compound collection led to the discovery of a novel series of N-substituted-5-aryl-oxazolidinones as potent human CCR8 antagonists. The synthesis, structure-activity relationships, and optimization of the series that led to the identification of SB-649701 (1a), are described.     

Racemic and chiral lactams as potent, selective and functionally active CCR4 antagonists

A series of racemic and chiral, nonracemic lactams that display high binding affinities, functional chemotaxis antagonism, and selectivity toward CCR4 are described. Compound 41, which provides reasonably high blood levels in mice when dosed intraperitoneally, was identified as a useful pharmacological tool to explore the role of CCR4 antagonism in animal models of allergic disease.     

Optimization of CCR4 antagonists: side-chain exploration

The design, synthesis, and activity of novel and selective small molecule antagonists of the CC chemokine receptor-4 (CCR4) are presented. Compound 8c was efficacious in a murine allergic inflammation model (ED(50) 30 mg/kg).