Discovery of a novel series of cyclic urea as potent CCR5 antagonists

A novel series of cyclic urea-based CCR5 antagonists was designed aiming to resolve instability issue in the fasted simulated intestinal fluid (FSIF) associated with the acyclic urea moiety in 1. This class of CCR5 compounds demonstrated high antiviral activities against HIV-1 infection in both HOS and PBL assays. Further evaluation of these compounds indicated that 16-R not only substantially enhanced its stability, but also exhibited excellent pharmacokinetics properties.     

Discovery of INCB10820/PF-4178903, a potent, selective, and orally bioavailable dual CCR2 and CCR5 antagonist

We report the discovery of a potent, selective, and orally bioavailable dual CCR2 and CCR5 antagonist (3S,4S)-N-[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]-3-methoxytetrahydro-2H-pyran-4-amine (19). After evaluation in 28-day toxicology studies, compound 19 (INCB10820/PF-4178903) was selected as a clinical candidate.     

Design and synthesis of pyridin-2-yloxymethylpiperidin-1-ylbutyl amide CCR5 antagonists that are potent inhibitors of M-tropic (R5) HIV-1 replication

A novel series of CCR5 antagonists were identified based on the redesign of Schering C. An SAR was established based on inhibition of CCR5 (RANTES) binding and these compounds exhibited potent inhibition of R5 HIV-1 replication in peripheral blood mononuclear cells.     

Design and synthesis of pyridin-2-ylmethylaminopiperidin-1-ylbutyl amide CCR5 antagonists that are potent inhibitors of M-tropic (R5) HIV-1 replication

A series of CCR5 antagonists were optimized for potent inhibition of R5 HIV-1 replication in peripheral blood mononuclear cells. Compounds that met acceptable ADME criteria, selectivity, human plasma protein binding, potency shift in the presence of α-glycoprotein were evaluated in rat and dog pharmacokinetics.     

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.     

Spiropiperidine CCR5 antagonists

A novel series of CCR5 antagonists has been identified, utilizing leads from high-throughput screening which were further modified based on insights from competitor molecules. Lead optimization was pursued by balancing opposing trends of metabolic stability and potency. Selective and potent analogs with good pharmacokinetic properties were successfully developed.     

Design and synthesis of novel small molecule CCR2 antagonists: Evaluation of 4-aminopiperidine derivatives

A novel N-(2-oxo-2-(piperidin-4-ylamino)ethyl)-3-(trifluoromethyl)benzamide series of human CCR2 chemokine receptor antagonists was identified. With a pharmacophore model based on known CCR2 antagonists a new core scaffold was designed, analogues of it synthesized and structure–affinity relationship studies derived yielding a new high affinity CCR2 antagonist N-(2-((1-(4-(3-methoxyphenyl)cyclohexyl)piperidin-4-yl)amino)-2-oxoethyl)-3-(trifluoromethyl)benzamide.     

The discovery of novel cyclohexylamide CCR2 antagonists

As a result of further SAR studies on a piperidinyl piperidine scaffold, we report the discovery of compound 44, a potent, orally bioavailable CCR2 antagonist. While having some in vitro hERG activity, this molecule was clean in an in vivo model of QT prolongation. In addition, it showed excellent efficacy when dosed orally in a transgenic murine model of acute inflammation.     

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.     

Alkylsulfone-containing trisubstituted cyclohexanes as potent and bioavailable chemokine receptor 2 (CCR2) antagonists

We describe novel alkylsulfones as potent CCR2 antagonists with reduced hERG channel activity and improved pharmacokinetics over our previously described antagonists. Several of these new alkylsulfones have a profile that includes functional antagonism of CCR2, in vitro microsomal stability, and oral bioavailability. With this improved profile, we demonstrate that two of these antagonists, 2 and 12, are orally efficacious in an animal model of inflammatory recruitment.     

Synthesis and evaluation of 2-phenyl-1,4-butanediamine-based CCR5 antagonists for the treatment of HIV-1

We describe the synthesis and potency of a novel series of N-substituted 2-phenyl- and 2-methyl-2-phenyl-1,4-diaminobutane- based CCR5 antagonists. Compounds 7a and 12f were found to be potent in anti-HIV assays and bioavailable in the low-dose rat PK model.     

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.     

Small molecule antagonists of CCR8 inhibit eosinophil and T cell migration

In this study, we demonstrate that in addition to T lymphocytes, human naïve eosinophils and the differentiated eosinophil-like cell line, AML14.3D10 express CCR8 and respond to CCL1 through CCR8 engagement. The responsiveness of cells was dependent on maturation stage, since CCL1 induced pronounced chemotaxis only in differentiated CCR8 positive AML14.3D10 cells. Despite the low CCR8 surface expression, human naïve eosinophils respond with a chemotaxis to high concentration CCL1. We further describe that Th2 clones in a maturation dependent fashion produce autocrine CCL1, which renders them unresponsive to further stimulation. An innovative method to enrich primary CCR8 reactive T cells was developed which demonstrates that primary peripheral CCR8 expressing T cells respond significantly to CCL1.We have developed novel small molecule CCR8 antagonists that are effective in inhibiting calcium mobilization and chemotaxis in differentiated AML cells as well as in human primary CCR8 positive T cells. Importantly, we demonstrate that the compounds can be divided into two subgroups: (i) compounds that are functional agonists for calcium mobilization and chemotaxis (ii) compounds that are pure antagonists. We demonstrate that agonism of these compounds does not correlate with their antagonistic potency. Taken together, we have identified a novel set of CCR8 compounds with antagonistic properties that inhibit CCL1 driven chemotaxis in both CCR8 expressing eosinophils as well as primary human T cells.     

Interaction of soluble CD4 with the chemokine receptor CCR5

The chemokine receptor CCR5 is constitutively associated with the T cell co-receptor CD4 in plasma cell membranes. The CD4-CCR5 complex exhibits distinct binding properties for macrophage inflammatory protein 1beta (MIP-1beta) and enhanced G-protein signaling as compared with those of CCR5 alone. Here we report that recombinant soluble CD4, when refolded into its dimeric form, allosterically modulates CCR5 and decreases the affinity for its natural ligand MIP-1beta. Monomeric soluble CD4 had little inhibitory effect on CCR5. In contrast, the two-domain amino-terminal fragment of soluble CD4 was able to completely inhibit the interaction of CCR5 with MIP-1beta. Thus, we suggest that various conformational states of CD4 exist, which differ markedly with regard to inhibiting the interaction of CCR5 with its ligand MIP-1beta. R5-tropic HIV-1 glycoprotein 120, but not interleukin-16, the natural agonist, or X4-tropic glycoprotein 120, inhibited MIP-1beta binding to CCR5 in the presence of monomeric and dimeric soluble CD4.     

The natural product CCR5 antagonist anibamine and its analogs as anti-prostate cancer agents

Prostate cancer is a leading cause of death among males in the United States. As the chemokine receptor CCR5 is over-expressed in more aggressive forms of prostate cancer, and is also a critical receptor in inflammation, chemokine receptor CCR5 antagonists could potentially act as anti-prostate cancer agents. Anibamine, a natural product CCR5 antagonist, provides a unique molecular scaffold for the generation of novel analogs with possible anti-prostate cancer activity. A series of analogs of anibamine were designed, synthesized and tested against several prostate cancer cell lines. The analogs all acted as CCR5 antagonists at micromolar range affinity to the receptor while their anti-proliferative activity varied depending on the cell line type and their chemical structural properties. Further basal cytotoxicity characterization on these compounds indicated some of them may be suitable for in vivo studies.     

Genetic diversity and prevalence of CCR2-CCR5 gene polymorphisms in the Omani population

Polymorphisms in the regulatory region of the CCR5 gene affect protein expression and modulate the progress of HIV-1 disease. Because of this prominent role, variations in this gene have been under differential pressure and their frequencies vary among human populations. The CCR2V64I mutation is tightly linked to certain polymorphisms in the CCR5 gene. The current Omani population is genetically diverse, a reflection of their history as traders who ruled extensive regions around the Indian Ocean. In this study, we examined the CCR2-CCR5 haplotypes in Omanis and compared the patterns of genetic diversity with those of other populations. Blood samples were collected from 115 Omani adults and genomic DNA was screened to identify the polymorphic sites in the CCR5 gene and the CCR2V64I mutation. Four minor alleles were common: CCR5-2554T and CCR5-2086G showed frequencies of 49% and 46%, respectively, whereas CCR5-2459A and CCR5-2135C both had a frequency of 36%. These alleles showed moderate levels of heterozygosity, indicating that they were under balancing selection. However, the well-known allele CCR5Δ32 was relatively rare. Eleven haplotypes were identified, four of which were common: HHC (46%), HHE (20%), HHA (14%) and HHF*2 (12%).     

Discovery and synthesis of 6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-one-based novel chemotype CCR2 antagonists via scaffold hopping strategy

The chemokine CC receptor subtype 2 (CCR2) has attracted intensive interest for drug development in diverse therapeutic areas, including chronic inflammatory diseases, diabetes, neuropathic pain, atherogenesis and cancer. By employing a cut-and-sew scaffold hopping strategy, we identified an active scaffold of 3,4-dihydro-2,6-naphthyridin-1(2H)-one as the central pharmacophore to derive novel CCR2 antagonists. Systematic structure–activity relationship study with respect to the ring size and the substitution on the naphthyridinone ring gave birth to 1-arylamino-6-alkylheterocycle-6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-ones as a brand new chemotype of CCR2 antagonists with nanomolar inhibitory activity. The best antagonism activity in this series was exemplified by compound 13a, which combined the optimal substitutions of 3,4-dichlorophenylamino at C-1 and 3-(4-(N-methylmethylsulfonamido)piperidin-1-yl)propyl at N-6 position, leading to an IC₅₀ value of 61?nM and 10-fold selectivity for CCR2 over CCR5. Efficient and general synthesis was established to construct the innovative core structure and derive the compound collections. This is the first report on our designed 6,7,8,9-tetrahydro-5H-pyrido[4,3-c]azepin-5-one as novel CCR2 antagonist scaffold and its synthesis.     

Design,synthesis and structure activity relationships of spirocyclic compounds as potent CCR1 antagonists

A series of CCR1 antagonists based upon spirocyclic compounds 1b and 2b were synthesised in which substituted aniline moiety was replaced with substituted benzamides. In vitro data revealed that CCR1 potency could be retained in such compounds.     

Discovery and biological profile of isoindolinone derivatives as novel metabotropic glutamate receptor 1 antagonists: A potential treatment for psychotic disorders

We describe here the discovery and biological profile of a series of isoindolinone derivatives as developed mGluR1 antagonists. Our combined strategy of rapid parallel synthesis and conventional medicinal optimization successfully led to N-cyclopropyl 22 and N-isopropyl isoindolinone analogs 21 and 23 with improved in vivo DMPK profiles. Moreover the most advanced analog 23 showed an oral antipsychotic-like effect at a dose of 1 mg/kg in an animal model.     

The discovery of BMS-457, a potent and selective CCR1 antagonist

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.