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Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors led to fused bi-heteroaryl hydantoin series that demonstrate sub-nanomolar potency (Ki) as well as excellent activity in human whole blood (hWBA). However, lead compound 2 posed some formulation challenges which prevented it for further development. A prodrug approach was investigated to address this issue. The pivalate prodrug 3 can be formulated as stable neutral form and demonstrated improved DMPK properties when compared with parent compound.

We have identified a series of hydantoin-derived TNF-a converting enzyme (TACE) inhibitors containing a pendant fused bi-heteroaryl group, which demonstrate sub-nanomolar potency (Ki), excellent activity in human whole blood assay, and improved DMPK profiles over prior series.

Introduction of nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzofuran inhibitor 2, resulted in the discovery of the more potent pyridofuran analogue 5. Subsequent introduction of small alkyl and alkoxy ligands into the pyridine ring resulted in further improvements in replicon potency. Replacement of the 4-chloro moiety on the pyrimidine core with a methyl group, and concomitant monoalkylation of the C-2 amino moiety resulted in the identification of several inhibitors with desirable characteristics. Inhibitor 41, from the monosubstituted pyridofuran and inhibitor 50 from the disubstituted series displayed excellent potency, selectivity (GAPDH/MTS CC(50)) and PK parameters in all species studied, while the selectivity in the thymidine incorporation assay (DNA·CC(50)) was low.

Based on a previously identified HCV replication (replicase) inhibitor 1 , SAR efforts were conducted around the pyrimidine core to improve the potency and pharmacokinetic profile of the inhibitors. A benzothiazole moiety was found to be the optimal substituent at the pyrimidine 5-position. Due to potential reactivity concern, the 4-chloro residue was replaced by a methyl group with some loss in potency and enhanced rat in vivo profile. Extensive investigations at the C-2 position resulted in identification of compound 16 that demonstrated very good replicon potency, selectivity and rodent plasma/target organ concentration. Inhibitor 16 also demonstrated good plasma levels and oral bioavailability in dogs, while monkey exposure was rather low. Chemistry optimization towards a practical route to install the benzothiazole moiety resulted in an efficient direct C–H arylation protocol.

Compound 1 was identified as a HCV replication inhibitor from screening/early SAR triage. Potency improvement was achieved via modulation of substituent on the 5-azo linkage. Due to potential toxicological concern, the 5-azo linkage was replaced with 5-alkenyl or 5-alkynyl moiety. Analogs containing the 5-alkynyl linkage were found to be potent inhibitors of HCV replication. Further evaluation identified compounds 53 and 63 with good overall profile, in terms of replicon potency, selectivity and in vivo characteristics. Initial target engagement studies suggest that these novel carbanucleoside-like derivatives may inhibit the HCV replication complex (replicase).

The SAR of a novel pyrazinyl-piperazinyl-piperidine scaffold with CXCR3 receptor antagonist activity was explored. Optimization of the DMPK profile and reduction of hERG inhibition is described. Compound 16e with single-digit CXCR3 affinity, good rat PK and hERG profiles has been identified as a lead for further study.

TNF-α converting enzyme (TACE) inhibitors are promising agents to treat inflammatory disorders and cancer. We have investigated novel tartrate diamide TACE inhibitors where the tartrate core binds to zinc in a unique tridentate fashion. Incorporating (R)-2-(2-N-alkylaminothiazol-4-yl)pyrrolidines into the left hand side amide of the tartrate scaffold led to the discovery of potent and selective TACE inhibitors, some of which exhibited good rat oral bioavailability.

Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors has led to an acetylene containing series that demonstrates sub-nanomolar potency (K(i)) as well as excellent activity in human whole blood. These studies led to the discovery of highly potent TACE inhibitors with good DMPK profiles.

We disclose further optimization of hydantoin TNF-alpha convertase enzyme (TACE) inhibitors. SAR with respect to the non-prime region of TACE active site was explored. A series of biaryl substituted hydantoin compounds was shown to have sub-nanomolar K(i), good rat PK, and good selectivity versus MMP-1, -2, -3, -7, -9, and -13.

The syntheses and structure-activity relationships of the tartrate-based TACE inhibitors are discussed. The optimization of both the prime and non-prime sites led to compounds with picomolar activity. Several analogs demonstrated good rat pharmacokinetics.

A series of non-imidazole histamine H(3) receptor antagonists based on the (3-phenoxypropyl)amine motif, which is a common pharmacophore for H(3) antagonists, has been identified. A preliminary SAR study around the amine moiety has identified 8a as a potent H(3) antagonist possessing a good pharmacokinetic profile in the rat.

More than 170 million people worldwide are affected by the hepatitis C virus (HCV). The disease has been described as a "silent epidemic" and "a serious global health crisis". HCV infection is a leading cause of chronic liver disease such as cirrhosis, carcinoma, or liver failure. The current pegylated interferon and ribavirin combination therapy is effective in only 50% of patients. Its moderate efficacy and apparent side effects underscore the need for safer and more effective treatments. The nonstructural NS3 protease of the virus plays a vital role in the replication of the HCV virus. The development of small molecule inhibitors of NS3 protease as antiviral agents has been intensively pursued as a viable strategy to eradicate HCV infection. However, it is a daunting task. The protease has a shallow and solvent-exposed substrate binding region, and the inhibitor binding energy is mainly derived from weak lipophilic and electrostatic interactions. Moreover, lack of a robust in vitro cell culture system and the absence of a convenient small animal model have hampered the assessment of both in vitro and in vivo efficacy of any antiviral compounds. Despite the tremendous challenges, with access to a recently developed cell-based replicon system, major progress has been made toward a more effective small molecule HCV drug. In our HCV program, facing no leads from our screening effort, a structure-based drug design approach was carried out. An alpha-ketoamide-type electrofile was designed to trap the serine hydroxyl of the protease. Early ketoamide inhibitors mimicked the structures of the peptide substrates. With the aid of X-ray structures, we successfully truncated the undecapeptide lead that had a molecular weight of 1265 Da stepwise to a tripeptide with a molecular weight of 500 Da. In an attempt to depeptidize the inhibitors, various strategies such as hydrazine urea replacement of amide bonds and P2 to P4 and P1 to P3 macrocyclizations were examined. Further optimization of the tripeptide inhibitors led to the identification of the best moieties for each site: primary ketoamide at P', cyclobutylalanine at P1, gem-dimethylcyclopropylproline at P2, tert-leucine at P3, and tert-butyl urea as capping agent. The combination of these led to the discovery of compound 8 (SCH 503034, boceprevir), our clinical candidate. It is a potent inhibitor in both enzyme assay (Ki* = 14 nM) and cell-based replicon assay (EC 90 = 0.35 microM). It is highly selective (2200x) against human neutrophil elastase (HNE). Boceprevir is well tolerated in humans and demonstrated antiviral activity in phase I clinical trials. It is currently in phase II trials. This Account details the complexity and challenges encountered in the drug discovery process.

Substituted quinolyl oxazoles were discovered as a novel and highly potent series of phosphodiesterase 4 (PDE4) inhibitors. Structure-activity relationship studies revealed that the oxazole core, with 4-carboxamide and 5-aminomethyl groups, is a novel PDE4 inhibitory pharmacophore. Selectivity profiles and in vivo biological activity are also reported.

A series of novel five- and six-membered ring urea derivatives have been described as potent and selective NK1 receptor antagonists. Several compounds in this series exhibited good oral activity and brain penetration. Syntheses of these compounds are also described herein.

We present the pharmacological and pharmacokinetic profiles of a novel histamine H3 receptor antagonist, N-(3,5-dichlorophenyl)-N′-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687). The H3-receptor binding Ki values for SCH 79687 were 1.9 and 13 nM in the rat and guinea pig (GP), respectively. The Ki values for SCH 79687 at histamine H1 and H2 receptors were greater than 1 μM. SCH 79687 showed a 41- and 82-fold binding selectivity for the H3 receptor over α2A-adrenoceptors and imidazoline I2, and >500-fold H3 selectivity compared with over 60 additional receptors. The pA2 value for SCH 79687 in the GP ileum electrical field-stimulated (EFS) contraction was 9.6 ± 0.3. Similar H3 antagonist activity was observed in the EFS cryopreserved and fresh tissue isolated human saphenous vein (HSV) assays (pKb = 9.4 ± 0.3 and 10.1 ± 0.4). SCH 79687 (30 nM) did not block clonidine-induced inhibition of EFS-induced contractions in HSV. SCH 79687 (ED50 = 0.3 mg/kg i.v.) attenuated (R)-α-methylhistamine inhibition of sympathetic hypertensive responses in the GP. At the time of activity evaluation, the GP plasma SCH 79687 concentration was 25 ng/ml at the dose of 0.3 mg/kg i.v. In feline nasal studies, combined administration of SCH 79687 (3 mg/kg i.v.) and the H1-antagonist loratadine (3 mg/kg i.v.), at individual doses that do not produce decongestion, inhibited the compound 48/80-induced congestion by 47%. The α-adrenergic agonist phenylpropanolamine (PPA; 1 mg/kg i.v.) also attenuated compound 48/80 nasal responses by 42%. Unlike the H3/H1 combination that did not affect blood pressure (BP), PPA (1 mg/kg i.v.) significantly increased BP compared with control animals by a maximum of 31 mm Hg. Orally, SCH 79687 (10 mg/kg) plus loratadine (10 mg/kg) also produced decongestion without effects on BP. In pharmacokinetic studies, oral dosing with SCH 79687 in the rat (10 mg/kg) and monkey (3 mg/kg) achieved plasma Cmax and area under the curve values greater than 1.5 and 12.1 μg · h/ml, respectively. SCH 79687 is an orally active H3 antagonist with a good pharmacokinetic profile that, in combination with an H1 antagonist, demonstrates decongestant efficacy comparable with oral sympathomimetic decongestants but without hypertensive liabilities.

The synthesis and binding affinity for hNK(1) and hNK(2) receptors of a series of diacyl substituted 2-aryl piperazines are described. SAR evaluation led to the racemic derivative 11g as an apparent dual inhibitor. Chiral chromatographic separation of 11g led to the observation that NK(1) activity was shown by one enantiomer (13a) and NK(2) activity was shown by the other enantiomer (13b). X-ray crystallographic analysis of the crystalline di-BOC derivative of the NK(2) active piperazine (15) showed that the 2R configuration was associated with NK(2) activity. Further derivatization indicated that dual NK(1)/NK(2) activity could be built into the 2R series.

Experiments were performed to characterize the pharmacology of SCH 206272 [(R,R)-1'[5-[(3,5-dichlorobenzoyl)methylamino]-3-(3,4-dichlorophenyl)-4(Z)-(methoxyimino)pentyl]-N-methyl-2-oxo-[1,4'bipiperidine]-3-acetamide] as a potent and selective antagonist of tachykinin (NK) NK(1), NK(2), and NK(3) receptors. SCH 206272 inhibited binding at human tachykinin NK(1), NK(2), and NK(3) receptors (K(i) = 1.3, 0.4, and 0.3 nM, respectively) and antagonized [Ca(2+)](i) mobilization in Chinese hamster ovary (CHO) cells expressing the cloned human tachykinin NK(1), NK(2), or NK(3) receptors. SCH 206272 inhibited relaxation of the human pulmonary artery (pK(b) = 7.7 +/- 0.3) induced by the tachykinin NK(1) receptor agonist, [Met-O-Me] substance P and contraction of the human bronchus (pK(b = 8.2 +/- 0.3) induced by the tachykinin NK(2) receptor agonist, neurokinin A. In isolated guinea pig tissues, SCH 206272 inhibited substance P-induced enhancement of electrical field stimulated contractions of the vas deferens, (pK(b = 7.6 +/- 0.2), NKA-induced contraction of the bronchus (pK(b) = 7.7 +/- 0.2), and senktide-induced contraction of the ileum. In vivo, oral SCH 206272 (0.1-10 mg/kg, p.o.) inhibited substance P-induced airway microvascular leakage and neurokinin A-induced bronchospasm in the guinea pig. In a canine in vivo model, SCH 206272 (0.1-3 mg/kg, p.o.) inhibited NK(1) and NK(2) activities induced by exogenous substance P and neurokinin A. Furthermore, in guinea pig models involving endogenously released tachykinins, SCH 206272 inhibited hyperventilation-induced bronchospasm, capsaicin-induced cough, and airway microvascular leakage induced by nebulized hypertonic saline. These data demonstrate that SCH 206272 is a potent, orally active tachykinin NK(1), NK(2), and NK(3) receptor antagonist. This compound may have beneficial effects in diseases thought to be mediated by tachykinins, such as cough, asthma, and chronic obstructive pulmonary disease.

To examine how B cell receptor affinity affects clonal selection in thymus-independent type 2 (TI-2) immune responses, we produced mice with antibodies that showed a 40-fold difference in affinity for the hapten (4-hydroxy-3-nitrophenyl)acetyl (NP). The difference in the responses of high- and low-affinity B cells to NP-Ficoll was only twofold. However, in competition experiments only the high-affinity B cells responded to antigen. CD19 deficiency increased the affinity threshold of TI-2 responses, whereas Lyn deficiency enhanced clonal expansion but abrogated B cell terminal differentiation. Thus, in TI-2 immune responses, large differences in affinity produce only small differences in the intrinsic ability of B cells to respond to antigen, and selection for high-affinity clones is due to clonal competition during the earliest stages of the response.

Receptor editing, clonal deletion, and anergy are the mechanisms by which B cells maintain tolerance to self antigens. To determine the extent to which receptor editing shapes the normal antibody repertoire, we generated an immunoglobulin κ polymorphism that facilitates the detection of editing of immunoglobulin light chains in vivo. We found that B cells are targeted for editing during a 2-hour delay in development at the pre-BII cell stage, and that about 25% of all antibody molecules are produced by gene replacement. These results suggest that receptor editing represents a major force in shaping the antibody repertoire.

Modification of prototype NK(1) antagonist 2 resulted in the synthesis of a series of simple amides 6 and retroamides 9. These compounds were shown to be potent and orally active NK(1) antagonists.

Functional probing of the backbone of the Sanofi NK2 antagonist SR 48968 has resulted in the discovery of two new classes of NK1/NK2 dual antagonists: the diamine class and the oxime class. The addition of the amino or the oxime functional group results in the reversal of the stereochemical preference of the NK2 receptor.

The structure-human CXCR3 binding affinity relationship of a series of pyridyl/pyrazinyl-piperazinyl-piperidine derivatives were explored with a focus to improve PK, hERG and metabolic profiles. Several small heterocycles were identified as amide surrogates, which minimized many potential metabolite issues. During the course of SAR development, we have observed the additive effect of desirable functional groups to improve hERG and PK profiles which lead to the discovery of many clinically developable CXCR3 antagonists with excellent overall profile.

The discovery of lead compound 2e was described. Its covalent binding to HCV NS5B polymerase enzyme was investigated by X-ray analysis. The results of distribution, metabolism and pharmacokinetics were reported. Compound 2e was demonstrated to be potent (replicon GT-1b EC50 = 0.003 μM), highly selective, and safe in in vitro and in vivo assays.

HCV infections are the leading causes for hepatocellular carcinoma and liver transplantation in the United States. Recent advances in drug discovery have identified direct acting antivirals which have significantly improved cure rates in patients. Current efforts are directed towards identification of novel direct acting antiviral targeting different mechanism of actions which could become part of all oral therapies. We recently disclosed the identification of a novel tricyclic indole derived inhibitors of HCV NS5B polymerase that bound to the enzyme close to the active site. In this manuscript we describe further optimization of potency and pharmacokinetics (PK) of these inhibitors to identify compounds in low nM potency against gt-1b. These analogs also demonstrate excellent PK in rats and monkeys when administered as a dimethyl ethyl amino ester prodrug.

A novel series of benzimidazolone-containing histamine H3-receptor antagonists were prepared and their structure-activity relationship was explored. These benzimidazolone analogs demonstrate potent H3-receptor binding affinities, no P450 enzyme inhibition, and strong H3 functional activity. Compound 1o exhibits the best overall profile with H3Ki=0.95nM and rat AUC=12.9μMh.

Gouty arthritis is a rheumatic disease that is characterized by the deposition of monosodium urate (MSU) in synovial joints cause by the increased serum hyperuricemia. This study used a three-dimensional (3D) flowing microfluidic chip to screen the effective candidate against MSU-stimulated human umbilical vein endothelial cell (HUVEC) damage, and found kinsenoside (Kin) to be the leading active component of Anoectochilus roxburghi, one of the Chinese medicinal plant widely used in the treatment of gouty arthritis clinically. Cell viability and apoptosis of HUVECs were evaluated, indicating that direct Kin stimulation and conditioned medium (CM) from Kin-treated macrophages both negatively modulated with MSU crystals. Additionally, Kin was capable of attenuating MSU-induced activation of nuclear factor-κB/mitogen-activated protein kinase (NF-κB/MAPK) signaling, targeting IκB kinase-α (IKKα) and IKKβ kinases of macrophages and influencing the expressions of NF-κB downstream cytokines and subsequent HUVEC bioactivity. Inflammasome NLR pyrin domain-containing 3 (NALP3) and toll-like receptor 2 (TLR2) were also inhibited after Kin treatment. Also, Kin downregulated CD14-mediated MSU crystals uptake in macrophages. In vivo study with MSU-injected ankle joints further revealed the significant suppression of inflammatory infiltration and endothelia impairment coupled with alleviation of ankle swelling and nociceptive response via Kin treatments. Taken together, these data implicated that Kin was the most effective candidate from Anoectochilus roxburghi to treat gouty arthritis clinically.

Combining the first generation H(1) antihistamine chlorpheniramine (1) with H(3) ligands of the alkylamine type has led to the identification of compound 9d, a dual ligand of both the H(1) and H(3) receptors.

Introduction of a nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzothiazole inhibitor 1 , resulted in the discovery of the more potent pyridothiazole analogues 3 . The potency and PK properties of the compounds were attenuated by the introductions of various functionalities at the R 1 , R 2 or R 3 positions of the molecule (compound 3 ). Inhibitors 38 and 44 displayed excellent potency, selectivity (GAPDH/MTS CC 50 ), PK parameters in all species studied, and cross genotype activity.

Starting from indole-based C-3 pyridone HCV NS5B polymerase inhibitor 2, structure-activity relationship (SAR) investigations of the indole N-1 benzyl moiety were performed. This study led to the discovery of irreversible inhibitors with p-fluoro-sulfone- or p-fluoro-nitro-substituted N-1 benzyl groups which achieved breakthrough replicon assay potency (EC(50) = 1 nM). The formation of a covalent bond with adjacent cysteine-366 thiol was was proved by mass spectroscopy and X-ray crystal structure studies. The C-5 ethyl C-2 carboxylic acid derivative 47 had an excellent oral area-under-the-curve (AUC) of 18 μM·h (10 mg/kg). Its oral exposure in monkeys and dogs was also very good. The NMR ALARM assay, mass spectroscopy experiments, in vitro counter screening, and toxicology assays demonstrated that the covalent bond formation between compound 47 and the protein was highly selective and specific. The overall excellent profile of 47 made it an interesting candidate for further investigation.

Starting with the indole-based C-3 pyridone lead HCV polymerase inhibitor 2, extensive SAR studies were performed at different positions of the indole core. The best C-5 groups were found to be compact and nonpolar moieties and that the C-6 attachments were not affecting potency. Limited N-1 benzyl-type substituent studies indicated that the best substitutions were fluoro or methyl groups at 2' or 5' positions of the benzyl group. To improve pharmacokinetic (PK) properties, acylsulfonamides were incorporated as acid isosteres at the C-2 position. Further optimization of the combination at N-1, C-2, C-5, and C-6 resulted in the identification of compound 56, which had an excellent potency in both NS5B enzyme (IC(50) = 0.008 μM) and cell-based replicon (EC(50) = 0.02 μM) assays and a good oral PK profile with area-under-the curve (AUC) of 14 and 8 μM·h in rats and dogs, respectively. X-ray structure of inhibitor 56 bound to the enzyme was also reported.

Optimization of oxazole-based PDE4 inhibitors has led to the discovery of a series of quinolyl oxazoles, with 4-benzylcarboxamide and 5-α-aminoethyl groups which exhibit picomolar potency against PDE4. Selectivity profiles and in vivo biological activity are also reported.

We report a series of potent imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors. Optimization of the solvent accessible 8-position led to improvements in both oral bioavailability and off-target kinase inhibition. Compound 25 demonstrates anti-tumor activity in an A2780 ovarian tumor xenograft model.

We report further expansion of the structure activity relationship (SAR) on the triaryl bis sulfone class of compounds (I), which are potent CB2 receptor ligands with excellent selectivity over the CB1 receptor. This study was extended to B ring changes, followed by simultaneous optimization of the A-, B-, and C-rings. Compound 42 has excellent CB2 potency, selectivity and rat exposure.

Hepatitis is a disease characterized by inflammation of the liver, usually producing swelling and, in many cases, permanent damage to liver tissues. Viral hepatitis C (HCV), a small (+)-RNA virus, infects chronically 3% of the world's population. Boceprevir, SCH 503034, (1) our first generation HCV inhibitor, has already established proof-of- concept and is currently in late stage (phase III) clinical trials. In view of the positive data from our first generation compound, further work aimed at optimizing its overall profile was undertaken. Herein, we report that extension of our earlier inhibitor to the P(4) pocket by introducing a new sulfonamide moiety and optimization of the P1/P(1)' capping led to the discovery of a novel series of inhibitors of the HCV NS3 serine protease. Optimization of the P(1) residue significantly improved potency and selectivity. The combination of optimal moieties led to the discovery of compound 47 which, in addition to being a potent inhibitor of HCV subgenomic RNA replication, was also found to have good PK profile in rat, dog and monkey.

The triaryl bis-sulfone 1 was modified by converting the aryl A-ring to a piperidine ring. The piperidine ring was further elaborated to a spirocyclopropyl piperidine moiety. The effect on CB2 binding potency, rat calcium channel affinity, and CYP 2C9 inhibition is described.

The hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The moderate efficacy along with side effects of the current pegylated interferon and ribavirin combination therapy underscores the need for more effective and safer new treatment. In an effort to improve upon our current clinical candidate, Boceprevir (SCH 503034), extensive SAR studies were performed on the P3 capping moieties. This led to the discovery of tert-leucinol derived cyclic imides as a potent series of novel P3 capping groups. Thus, the introduction of these imide caps improved the cell-based replicon EC(90) by more than 10-fold. A number of imides with various substitutions, ring sizes, bicyclic systems, and heterocyclic rings were explored. The 4,4-dimethyl substituted glutarimide emerged as the best cap as exemplified in compound 21 (K(i)* = 4 nM, EC(90) = 40 nM). Systematic optimization of different positions (P', P3, and P1) of the inhibitor resulted in the identification of the lead compound 46, which had an excellent potency (K(i)* = 4 nM, EC(90) = 30 nM) and good pharmacokinetic profile (22% and 35% bioavailability in rats and dogs, respectively). X-ray structure of inhibitor 46 bound to the enzyme revealed that there was an additional hydrogen bonding interaction between one of the imide carbonyls and Cys159.

We have used [3H]N alpha-methylhistamine to characterize H3-binding in the guinea pig brain and to study its tissue distribution. Kinetic and equilibrium binding experiments indicate a single class of high affinity sites in membranes isolated from guinea pig brain tissue (Kd = 0.4 nM, Bmax = 41 fmol/mg of protein). Competition binding experiments have confirmed that this ligand associates with H3-receptors and, under the conditions used in these experiments, does not bind to H1- or H2-receptors. Although there was some binding in the ileum and large intestine, H3-binding was found primarily in the central nervous system.

Structure-activity relationship on our recently reported triaryl bis-sulfone class of cannabinoid-2 (CB2) receptor selective inverse agonists was explored. Modifications to the methane sulfonamide, substitutions to B and C phenyl rings, and replacements of the C-ring were investigated. A compound with excellent CB2 activity, selectivity for CB2 over CB1, and in vivo plasma levels was identified.

A series of novel cyclobutane derivatives as potent and selective NK1 receptor antagonists is described. Several compounds in this series exhibited high in vitro binding affinity (Ki

A novel series of histamine H3 receptor antagonists based on the 4-[(1H-imidazol-4-yl)methyl]piperidine template displaying low CYP2D6 and CYP3A4 inhibitory profiles has been identified. Structural features responsible for the reduction of P450 activity, a typical liability of 4-substituted imidazoles, have been established.

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.

The mammalian tachykinin (TK) peptides and their three neurokinin (NK) receptors represent an effector system with wide-ranging actions on neuronal, airway smooth muscle, mucosal, endothelial, immune, inflammatory and remodeling cell function. Recent clinical and preclinical data suggests pathophysiological relevance for TKs in various diseases including asthma, emesis and depression. The promiscuous TK-NK receptor interactions and incompletely overlapping functions mediated by each NK receptor may indicate added therapeutic benefit of using multiple NK receptor blockade. Consequently, there has been substantial pharmaceutical effort in projects to develop nonpeptide dual and triple NK receptor antagonists. This review identifies the chemical and biological approach used to develop a TK antagonist active at the three NK receptors. Clinical activity has been observed using single and/or dual NK receptor antagonists in asthma, depression/anxiety and, most notably, emesis trials but no compound with mono or multiple NK receptor antagonist activities has cleared all the development and regulatory hurdles to commercialization. Current experience indicates that potent dual and triple NK receptor-selective antagonists possessing appropriate affinity and pharmacokinetic properties can be developed. As an example, the biological and pharmacokinetic profiles of a new representative of this class of agent, SCH 206272, is detailed in the present review. Whether such agents will fulfill researchers' expectations must await further clinical trials.

The synthesis and pharmacological profile of a novel series of 2-substituted 8-methoxyquinolines is described. The 2-trifluoromethyl compound was found to be a potent inhibitor of phosphodiesterase type 4 (PDE4).

The syntheses and pharmacological profiles of some 2-trifluoromethyl-8-methoxyquinoline-5-carboxamides are described. SCH351591 is a potent selective inhibitor of phosphodiesterase type 4 (PDE4).

Antibody affinity for antigen is believed to govern B lymphocyte selection during T-dependent immune responses. To examine antibody affinity in T cell dependent immune responses, we compared mice that carry targeted V(H)B1-8 antibody genes with high or low antigen-binding affinity. We found that high- and low-affinity B cells had the same intrinsic capacity to respond to antigen, but in experiments where limiting numbers of high- and low-affinity B cells were mixed in wild-type recipient mice, only the high-affinity B cells accumulated in germinal centers (GCs). In GCs, high-affinity B cells accumulated fewer V(H) somatic mutations than low affinity B cells. This effect was due to selections as the frequency of mutation in noncoding immunoglobulin gene DNA is the same in high- and low- affinity B cells. Thus, B cells recruited to the GC appeared to undergo a fixed mutation program, regardless of initial B cell receptor affinity. We conclude that in addition to the selection that occurs in GCs, stringent selection for high-affinity clones is also imposed in the early stages of the T cell dependent immune response in vivo.

A series of 5-[(3,5-bis(trifluoromethyl)phenyl)methoxy]-3-(3,4-dichlorophenyl)-4(Z)-(methoxyimino)pentyl-1-piperazines was prepared and their affinity for the NK1 and NK2 receptors investigated. Compounds 7f, 10o, 10r, and 10s were found to be our most potent inhibitors.