Advanced Clinical Candidates Research Articles

Toward better cures for Mycobacterium abscessus lung disease.

SUMMARYThe opportunistic pathogen Mycobacterium abscessus (Mab) causes fatal lung infections that bear similarities-and notable differences-with tuberculosis (TB) pulmonary disease. In contrast to TB, no antibiotic is formally approved to treat Mab disease, there is no reliable cure, and the discovery and development pipeline is incredibly thin. Here, we discuss the factors behind the unsatisfactory cure rates of Mab disease, namely intrinsic resistance and persistence of the pathogen, and the use of underperforming, often parenteral and toxic, repurposed drugs. We propose preclinical strategies to build injectable-free sterilizing and safe regimens: (i) prioritize oral bactericidal antibiotic classes, with an initial focus on approved agents or advanced clinical candidates to provide immediate options for desperate patients, (ii) test drug combinations early, (iii) optimize novel leads specifically for M. abscessus, and (iv) consider pharmacokinetic-pharmacodynamic targets at the site of disease, the lung lesions in which drug tolerant bacterial populations reside. Knowledge and tool gaps in the preclinical drug discovery process are identified, including validated mouse models and computational platforms to enable in vitro mouse-human translation. We briefly discuss recent advances in clinical development, the need for readouts and biomarkers that correlate with cure, and clinical trial concepts adapted to the uniqueness of Mab patient populations for new regimen development. In an era when most pharmaceutical firms have withdrawn from antimicrobial drug discovery, the breakthroughs needed to fill the regimen development pipeline will likely come from partnerships between academia, biotech, pharma, non-profit organizations, and governments, with incentives that reward cooperation.

Evaluation of a Selective Chemical Probe Validates That CK2 Mediates Neuroinflammation in a Human Induced Pluripotent Stem Cell-Derived Mircroglial Model.

Novel treatments for neurodegenerative disorders are in high demand. It is imperative that new protein targets be identified to address this need. Characterization and validation of nascent targets can be accomplished very effectively using highly specific and potent chemical probes. Human induced pluripotent stem cells (hiPSCs) provide a relevant platform for testing new compounds in disease relevant cell types. However, many recent studies utilizing this platform have focused on neuronal cells. In this study, we used hiPSC-derived microglia-like cells (MGLs) to perform side-by-side testing of a selective chemical probe, SGC-CK2-1, compared with an advanced clinical candidate, CX-4945, both targeting casein kinase 2 (CK2), one of the first kinases shown to be dysregulated in Alzheimer’s disease (AD). CK2 can mediate neuroinflammation in AD, however, its role in microglia, the innate immune cells of the central nervous system (CNS), has not been defined. We analyzed available RNA-seq data to determine the microglial expression of kinases inhibited by SGC-CK2-1 and CX-4945 with a reported role in mediating inflammation in glial cells. As proof-of-concept for using hiPSC-MGLs as a potential screening platform, we used both wild-type (WT) MGLs and MGLs harboring a mutation in presenilin-1 (PSEN1), which is causative for early-onset, familial AD (FAD). We stimulated these MGLs with pro-inflammatory lipopolysaccharides (LPS) derived from E. coli and observed strong inhibition of the expression and secretion of proinflammatory cytokines by simultaneous treatment with SGC-CK2-1. A direct comparison shows that SGC-CK2-1 was more effective at suppression of proinflammatory cytokines than CX-4945. Together, these results validate a selective chemical probe, SGC-CK2-1, in human microglia as a tool to reduce neuroinflammation.

Randomised trial of the P2X3 receptor antagonist sivopixant for refractory chronic cough.

BackgroundThe purinoceptor subtype P2X3 has been shown to have significant involvement in the cough reflex; the heterotrimer version of the purinoceptor (P2X2/3) has been implicated in taste disturbance. The most advanced clinical candidate antagonist gefapixant has low selectivity among P2X3 receptors and induced taste disturbance, whereas newly developed sivopixant has high selectivity towards P2X3 versus P2X2/3.MethodsIn a phase 2a, randomised, double-blind, placebo-controlled, crossover, multicentre study, adult patients with refractory or unexplained chronic cough received oral sivopixant 150 mg or placebo once daily for 2 weeks, followed by a 2–3-week washout period, and then crossed over to placebo or sivopixant for 2 weeks. Efficacy and safety of sivopixant were evaluated.ResultsOf 31 randomised patients, 15 in the sivopixant-first group and 15 in the placebo-first group completed the study. After 2 weeks of treatment, the placebo-adjusted ratios of the average hourly number of coughs to baseline during daytime (primary end-point) and over 24 h (secondary end-point) were −31.6% (p=0.0546) and −30.9% (p=0.0386), respectively. Sivopixant also improved health-related quality of life. Treatment-related adverse events occurred in 12.9% and 3.2% of patients during sivopixant and placebo administration, respectively. Mild taste disturbance occurred in two patients (6.5%) during sivopixant administration.ConclusionsSivopixant reduced objective cough frequency and improved health-related quality of life, with a low incidence of taste disturbance, among patients with refractory or unexplained chronic cough.

Analyzing the scaffold diversity of cyclin-dependent kinase inhibitors and revisiting the clinical and preclinical pipeline.

Kinases have gained an important place in the list of vital therapeutic targets because of their overwhelming clinical success in the last two decades. Among various clinically validated kinases, the cyclin-dependent kinases (CDK) are one of the extensively studied drug targets for clinical development. Food and Drug Administration has approved three CDK inhibitors for therapeutic use, and at least 27 inhibitors are under active clinical development. In the last decade, research and development in this area took a rapid pace, and thus the analysis of scaffold diversity is essential for future drug design. Available reviews lack the systematic study and discussion on the scaffold diversity of CDK inhibitors. Herein we have reviewed and critically analyzed the chemical diversity present in the preclinical and clinical pipeline of CDK inhibitors. Our analysis has shown that although several scaffolds represent CDK inhibitors, only the amino-pyrimidine is a well-represented scaffold. The three-nitrogen framework of amino-pyrimidine is a fundamental hinge-binding unit. Further, we have discussed the selectivity aspects among CDKs, the clinical trial dose-limiting toxicities, and highlighted the most advanced clinical candidates. We also discuss the changing paradigm towards selective inhibitors and an overview of ATP-binding pockets of all druggable CDKs. We carefully analyzed the clinical pipeline to unravel the candidates that are currently under active clinical development. In addition to the plenty of dual CDK4/6 inhibitors, there are many selective CDK7, CDK9, and CDK8/19 inhibitors in the clinical pipeline.

Discovery and development of CPL207280 as new GPR40/FFA1 agonist

Due to a unique mechanism that limits the possibility of hypoglycemia, the free fatty acid receptor (FFA1) is an attractive target for the treatment of type 2 diabetes. So far, however, none of the promising agonists have been able to enter the market. The most advanced clinical candidate, TAK-875, was withdrawn from phase III clinical trials due to liver safety issues. In this article, we describe the key aspects leading to the discovery of CPL207280 (13), the design of which focused on long-term safety. The introduction of small, nature-inspired acyclic structural fragments resulted in compounds with retained high potency and a satisfactory pharmacokinetic profile. Optimized synthesis and upscaling provided a stable, solid form of CPL207280-51 (45) with the properties required for the toxicology studies and ongoing clinical trials.

Azaindole therapeutic agents

Azaindole structural framework is an integral part of several biologically active natural and synthetic organic molecules; and several FDA approved drugs for various diseases. In the last decade, quite a number of literature reports appeared describing the pharmacology, biological activity and therapeutic applications of a variety of azaindole molecules. This prompted the organic and medicinal chemistry community to develop novel synthetic methods for various azaindoles and test them for a bioactivity against a variety of biological targets. Herein, we have summarized the biological activity of therapeutically advanced clinical candidates and several preclinical candidate drugs that contain azaindole structural moiety.

Off-target based drug repurposing opportunities for tivantinib in acute myeloid leukemia

GSK3α has been identified as a new target in the treatment of acute myeloid leukemia (AML). However, most GSK3 inhibitors lack specificity for GSK3α over GSK3β and other kinases. We have previously shown in lung cancer cells that GSK3α and to a lesser extent GSK3β are inhibited by the advanced clinical candidate tivantinib (ARQ197), which was designed as a MET inhibitor. Thus, we hypothesized that tivantinib would be an effective therapy for the treatment of AML. Here, we show that tivantinib has potent anticancer activity across several AML cell lines and primary patient cells. Tivantinib strongly induced apoptosis, differentiation and G2/M cell cycle arrest and caused less undesirable stabilization of β-catenin compared to the pan-GSK3 inhibitor LiCl. Subsequent drug combination studies identified the BCL-2 inhibitor ABT-199 to synergize with tivantinib while cytarabine combination with tivantinib was antagonistic. Interestingly, the addition of ABT-199 to tivantinib completely abrogated tivantinib induced β-catenin stabilization. Tivantinib alone, or in combination with ABT-199, downregulated anti-apoptotic MCL-1 and BCL-XL levels, which likely contribute to the observed synergy. Importantly, tivantinib as single agent or in combination with ABT-199 significantly inhibited the colony forming capacity of primary patient AML bone marrow mononuclear cells. In summary, tivantinib is a novel GSK3α/β inhibitor that potently kills AML cells and tivantinib single agent or combination therapy with ABT-199 may represent attractive new therapeutic opportunities for AML.

Abstract 5860: Novel, first-in-class dual inhibitors of lysine specific demethylase 1 (LSD1) and histone deacetylatse 1 (HDAC) for treatment of cancer

Abstract Introduction: LSD1 is a flavin adenine dinucleotide (FAD)-dependent amine oxidase that removes methyl groups from mono- or dimethylated histone H3 lysine 4. Studies have shown that LSD1 contributes to acute myelogenous leukaemia pathogenesis and patients that are non responders to ATRA respond to LSD1-ATRA combination treatment in clinic. Recent studies have shown that there is cross-talk between two components of CoREST complex, LSD1 and HDAC1/2 and combined inhibition of these targets has been shown to be more efficacious in multiple cancers. Therefore, dual inhibitors targeting both LSD1 and HDAC could be useful in treating cancers. To test the hypothesis, we have developed a set of molecules that have dual activity on LSD1 and HDACs. Methods: To assess in vitro LSD1potency, TR-FRET assay was used. For assessing HDAC activity fluorescence based HDAC activity assay was performed. Western blotting and RT-qPCR were used to assess biomarkers of LSD1 and HDAC1/2 inhibition. Alamar blue cytotoxicity assay was used to assess cell proliferation. Xenograft models were used to assess in vivo efficacy. Results: Dual inhibitors show strong in vitro potency comparable to advanced clinical candidates, against LSD1. On HDAC1/2 these molecules showed comparable IC50 as marketed HDAC1/2 specific drugs. Interestingly, these dual inhibitors lead to stronger and complete inhibition of cell proliferation in broader types of cancer cell lines, including, acute myeloid leukemia, multiple myeloma, hepatocellular carinoma and small cell lung cancer when compared to LSD1 specific inhibitor GSK2879552. Target engagement studies confirm the concomitant increase in mRNA levels of GFI1b, CD11b, CD86 and H3K9 acetylation levels. In vitro activity also shows a clear translation in efficacy studies. JBI128, one of the lead molecules from this series was tested in multiple in vivo studies, including, non-small cell and small cell lung cancer, where it not only shows single agent activity, but can also be combined with other targeted agents or SoC safely. In addition, combination of JBI128 with immune checkpoint inhibitor anti-PDL1 antibody in the CT26 syngeneic model showed much stronger efficacy as compared to either of the single agents. This clearly suggests that these dual inhibitors in addition to being epigenetic modulators in the cancer cells also have a role in immune modulation thereby contributing to stronger efficacy. Further studies in terms of gene expression analysis are underway to understand the molecular mechanism behind the additional activity/efficacy of these dual inhibitors. Conclusion: These LSD1-HDAC dual inhibitors have the potential to be developed as first-in-class therapies that could offer stronger clinical efficacy compared to LSD1 or HDAC inhibitor alone. Further mechanistic and combination studies with standard therapies are in progress. Citation Format: Dhanalakshmi Sivanandhan, Sreekala Nair, Subramaniyam Tantry, Sridharan Rajagopal, Mahanandeesha Hallur, Kannan M, Srinatha KC, Damodara K, Dilipkumar M, Chandru G, Dimpy Ghosh, Pradeep N, Anuj Kumar Singh, Mohd Zainuddin, Rudresh G, Radha Sharma, Meghashree S, Durga P. Kumar, Purushottam Dewang, Sriram Rajagopal. Novel, first-in-class dual inhibitors of lysine specific demethylase 1 (LSD1) and histone deacetylatse 1 (HDAC) for treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5860.

CC-401 Promotes β-Cell Replication via Pleiotropic Consequences of DYRK1A/B Inhibition.

Pharmacologic expansion of endogenous β cells is a promising therapeutic strategy for diabetes. To elucidate the molecular pathways that control β-cell growth we screened ∼2400 bioactive compounds for rat β-cell replication-modulating activity. Numerous hit compounds impaired or promoted rat β-cell replication, including CC-401, an advanced clinical candidate previously characterized as a c-Jun N-terminal kinase inhibitor. Surprisingly, CC-401 induced rodent (in vitro and in vivo) and human (in vitro) β-cell replication via dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) 1A and 1B inhibition. In contrast to rat β cells, which were broadly growth responsive to compound treatment, human β-cell replication was only consistently induced by DYRK1A/B inhibitors. This effect was enhanced by simultaneous glycogen synthase kinase-3β (GSK-3β) or activin A receptor type II-like kinase/transforming growth factor-β (ALK5/TGF-β) inhibition. Prior work emphasized DYRK1A/B inhibition-dependent activation of nuclear factor of activated T cells (NFAT) as the primary mechanism of human β-cell-replication induction. However, inhibition of NFAT activity had limited effect on CC-401-induced β-cell replication. Consequently, we investigated additional effects of CC-401-dependent DYRK1A/B inhibition. Indeed, CC-401 inhibited DYRK1A-dependent phosphorylation/stabilization of the β-cell-replication inhibitor p27Kip1. Additionally, CC-401 increased expression of numerous replication-promoting genes normally suppressed by the dimerization partner, RB-like, E2F and multivulval class B (DREAM) complex, which depends upon DYRK1A/B activity for integrity, including MYBL2 and FOXM1. In summary, we present a compendium of compounds as a valuable resource for manipulating the signaling pathways that control β-cell replication and leverage a DYRK1A/B inhibitor (CC-401) to expand our understanding of the molecular pathways that control β-cell growth.

Abstract B105: ACTR707: a novel T-cell therapy for the treatment of relapsed or refractory CD20+ B cell lymphoma in combination with rituximab

Abstract The Antibody-Coupled T-cell Receptor (ACTR) platform is an autologous engineered T-cell therapy developed to combine with tumor-targeting antibodies to exert potent antitumor immune responses and tumor cell killing. The ACTR construct is composed of the extracellular domain of CD16 (FCGR3A; high-affinity V158 variant) linked to CD3ζ signaling and costimulatory domains. ACTR-expressing T cells are universal, and can be flexibly paired with desired therapeutic antibodies to target tumor antigens. Unum’s most advanced clinical candidate, ACTR087, is currently in clinical testing in combination with rituximab for the treatment of CD20+ B cell lymphoma (NCT02776813). To expand upon the ACTR platform, over 90 different domain-modified variant ACTRs were generated and evaluated through rigorous in vitro and in vivo testing in combination with a broad range of tumor-targeting antibodies for use in hematologic and solid tumor indications. ACTR T-cell cytotoxicity, cytokine release and proliferation assays, combined with performance in an in vitro repeated stimulation “stress test,” led to the identification of several lead ACTR candidates. The final ACTR candidate was identified on the ability to mediate tumor regressions of aggressive CD20+ lymphomas and HER2+ solid tumors in vivo when combined with rituximab or trastuzumab, respectively. These efforts identified ACTR707, an ACTR construct containing a CD28 costimulatory domain with additional molecular elements. Here we present nonclinical data supporting an ongoing first-in-human phase 1 clinical trial of ACTR707 in combination with rituximab. When combined with rituximab, ACTR707 T cells had potent activation, proliferation, cytokine production, and tumor-directed cytotoxicity in the presence of CD20+ lymphoma cell lines. ACTR707 T-cell in vitro activity was dependent on rituximab and was dose-titratable. ACTR707 T cells had potent antitumor efficacy in vivo in an aggressive Raji lymphoma xenograft model in NSG mice; ACTR707 T cell antitumor activity was ACTR T cell and rituximab dose-dependent, with higher T-cell numbers and antibody concentrations mediating improved responses. Further, ACTR707 in combination with rituximab outperformed a CD19 targeted CAR-T against aggressive Raji tumors in vivo. Taken together, these nonclinical data demonstrate the specificity and versatility of the ACTR707 T-cell therapeutic approach to target diverse cancer antigens and directly supports clinical testing in combination with rituximab. The phase I study, ATTCK-20-03 (NCT03189836), in subjects with relapsed or refractory CD20+ B cell lymphoma is a multicenter, single-arm, open-label dose escalation study evaluating the safety and antilymphoma efficacy of ACTR707 T cells in combination with rituximab. Subjects who meet eligibility requirements with histologically confirmed relapsed or refractory CD20+ B cell lymphoma of one of the following histologic subtypes are eligible: DLBCL, MCL, PMBCL, Gr3b-FL, TH-FL. The study’s primary objective is to assess the safety of the combination and define dose recommendations for further study. Additional study objectives include the assessment of antilymphoma activity, ACTR707 persistence, ACTR707 product characterization, inflammatory laboratory assessments, and rituximab pharmacokinetics. Enrollment is ongoing. Citation Format: Greg Motz, Kathleen Whiteman, John Shin, Tapasya Pai, Casey Judge, Anthony Barnitz, James Hemphill, James Kim, Ann Ranger, Heather Huet, Kathleen McGinness, Birgit Schultes, Geoffrey Hodge, Michael Vasconcelles, Seth Ettenberg. ACTR707: a novel T-cell therapy for the treatment of relapsed or refractory CD20+ B cell lymphoma in combination with rituximab [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B105.

Cover Picture: Novel Pieces for the Emerging Picture of Sulfoximines in Drug Discovery: Synthesis and Evaluation of Sulfoximine Analogues of Marketed Drugs and Advanced Clinical Candidates (ChemMedChem 7/2017)

Cover Picture: Novel Pieces for the Emerging Picture of Sulfoximines in Drug Discovery: Synthesis and Evaluation of Sulfoximine Analogues of Marketed Drugs and Advanced Clinical Candidates (ChemMedChem 7/2017)

Novel Pieces for the Emerging Picture of Sulfoximines in Drug Discovery: Synthesis and Evaluation of Sulfoximine Analogues of Marketed Drugs and Advanced Clinical Candidates.

Sulfoximines have gained considerable recognition as an important structural motif in drug discovery of late. In particular, the clinical kinase inhibitors for the treatment of cancer, roniciclib (pan‐CDK inhibitor), BAY 1143572 (P‐TEFb inhibitor), and AZD 6738 (ATR inhibitor), have recently drawn considerable attention. Whilst the interest in this underrepresented functional group in drug discovery is clearly on the rise, there remains an incomplete understanding of the medicinal‐chemistry‐relevant properties of sulfoximines. Herein we report the synthesis and in vitro characterization of a variety of sulfoximine analogues of marketed drugs and advanced clinical candidates to gain a better understanding of this neglected functional group and its potential in drug discovery.

The Susceptibility of Trypanosomatid Pathogens to PI3/mTOR Kinase Inhibitors Affords a New Opportunity for Drug Repurposing

BackgroundTarget repurposing utilizes knowledge of “druggable” targets obtained in one organism and exploits this information to pursue new potential drug targets in other organisms. Here we describe such studies to evaluate whether inhibitors targeting the kinase domain of the mammalian Target of Rapamycin (mTOR) and human phosphoinositide-3-kinases (PI3Ks) show promise against the kinetoplastid parasites Trypanosoma brucei, T. cruzi, Leishmania major, and L. donovani. The genomes of trypanosomatids encode at least 12 proteins belonging to the PI3K protein superfamily, some of which are unique to parasites. Moreover, the shared PI3Ks differ greatly in sequence from those of the human host, thereby providing opportunities for selective inhibition.Methodology/Principal FindingsWe focused on 8 inhibitors targeting mTOR and/or PI3Ks selected from various stages of pre-clinical and clinical development, and tested them against in vitro parasite cultures and in vivo models of infection. Several inhibitors showed micromolar or better efficacy against these organisms in culture. One compound, NVP-BEZ235, displayed sub-nanomolar potency, efficacy against cultured parasites, and an ability to clear parasitemia in an animal model of T. brucei rhodesiense infection.Conclusions/SignificanceThese studies strongly suggest that mammalian PI3/TOR kinase inhibitors are a productive starting point for anti-trypanosomal drug discovery. Our data suggest that NVP-BEZ235, an advanced clinical candidate against solid tumors, merits further investigation as an agent for treating African sleeping sickness.

Identification of MK-5710 ((8aS)-8a-methyl-1,3-dioxo-2-[(1S,2R)-2-phenylcyclopropyl]-N-(1-phenyl-1H-pyrazol-5-yl)hexahydroimid azo[1,5-a]pyrazine-7(1H)-carboxamide), a potent smoothened antagonist for use in Hedgehog pathway dependent malignancies, Part 1

The Hedgehog (Hh-) signaling pathway is a key developmental pathway which controls patterning, growth and cell migration in most tissues, but evidence has accumulated showing that many human tumors aberrantly reactivate this pathway. Smoothened antagonists offer opportunities for the treatment of malignancies dependent on the Hh pathway, and the most advanced clinical candidates are demonstrating encourage initial results. A novel series of [6,5]-bicyclic tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-dione smoothened antagonists has been identified, and the series has been extensively explored to ascertain the key detriments for activity, demonstrating that the trans-2-phenylcyclopropyl and hydantoin ring systems are critical for potency, while a variety of urea substituents can be tolerated. The combination of these optimal groups gives smoothened antagonists with activity in the low nanomolar range.

Neuronal Nicotinic Acetylcholine Receptors - Targets for the Development of Drugs to Treat Cognitive Impairment Associated with Schizophrenia and Alzheimers Disease

Nicotinic acetylcholine receptors (nAChR) have been strongly implicated as therapeutic targets for treating cognitive deficits in disorders such as schizophrenia and Alzheimer's disease (AD). In particular alpha7 and alpha4beta2 subtype-selective nAChR agonists and partial agonists have been developed as potential candidates for the treatment of schizophrenia, cognitive disorders (including Alzheimer's disease), and inflammation. Further development of positive allosteric modulators and antagonists were also recently reported in the literature. In this review we will cover recent developments focused on the above mentioned nAChR subtypes, starting from the most advanced clinical candidate followed by an overview of literature compounds where potency, selectivity, central nervous system access, pharmacological activity and pharmacokinetic properties are disclosed.

Use of Artificial Intelligence in the Design of Small Peptide Antibiotics Effective against a Broad Spectrum of Highly Antibiotic-Resistant Superbugs

Increased multiple antibiotic resistance in the face of declining antibiotic discovery is one of society's most pressing health issues. Antimicrobial peptides represent a promising new class of antibiotics. Here we ask whether it is possible to make small broad spectrum peptides employing minimal assumptions, by capitalizing on accumulating chemical biology information. Using peptide array technology, two large random 9-amino-acid peptide libraries were iteratively created using the amino acid composition of the most active peptides. The resultant data was used together with Artificial Neural Networks, a powerful machine learning technique, to create quantitative in silico models of antibiotic activity. On the basis of random testing, these models proved remarkably effective in predicting the activity of 100,000 virtual peptides. The best peptides, representing the top quartile of predicted activities, were effective against a broad array of multidrug-resistant "Superbugs" with activities that were equal to or better than four highly used conventional antibiotics, more effective than the most advanced clinical candidate antimicrobial peptide, and protective against Staphylococcus aureus infections in animal models.

Vasopressin Antagonists as Anxiolytics and Antidepressants: Recent Developments

A compelling case for the potential utility of vasopressin (AVP) antagonists as a novel therapeutic class for the treatment of stress-related affective illness has emerged based on observations in depressed individuals, findings in animal models of anxiety and depression, and an understanding of changes in hypothalamic-pituitary-adrenal (HPA) axis regulation under chronic stress. The scientific bases for vasopressin antagonists as a pharmacotherapy for anxiety and depression include: 1) the neuroadaptation and dysregulation of HPA function that accompanies chronic stress in affected humans and in animal models of anxiety and depression, 2) recognition that AVP, not corticotrophin releasing factor (CRF), drives HPA function associated with chronic psychological stress, 3) the CNS localization of vasopressin V1a and V1b receptors in limbic system regions involved in HPA regulation and control of social behaviors, and 4) preclinical data showing efficacy in animal models employed as screens for anxiolytic and antidepressant activity. The public health need for new pharmaceutical treatments for stress-related affective illness is well documented. In the United States alone, anxiety and depression affect some 40 million people each year and carry a conservatively estimated annual total economic burden of at least $125 billion. Existing pharmacotherapies for both indications are not uniformly effective and frequently have undesirable side effects. These limitations demonstrate that a new treatment approach through vasopressin receptor antagonism in the CNS may offer significant opportunities for improved outcomes. In this review, the development of compounds in this class since 2005 is considered. The most advanced clinical candidates and newer compounds described in recent patents are presented.

The Discovery and Exploratory Development of Maraviroc (UK-427,857): A Novel CCR5 Antagonist for the Treatment of HIV

Maraviroc is a novel CCR5 antagonist and is the most advanced clinical candidate in Pfizer's CCR5 discovery and development programme. It is exquisitely selective for the CCR5 receptor and demonstrates potent activity in vitro against both lab-adapted and primary clinical HIV isolates spanning all of the clades, including viruses that are resistant to current classes of HIV agents. Maraviroc has been evaluated in >400 volunteers and in 66 HIV patients where it is well tolerated at doses in excess of those required to block the CCR5 receptor and those providing free drug levels above the in vitro concentrations for potent antiviral activity. Consistent with this, Maraviroc has demonstrated encouraging short-term (10 day), single agent efficacy as measured by reductions in viral loads in asymptomatic HIV patients; doses of 300 mg QD and 300 mg BID resulted in mean maximum HIV RNA reductions of 1.60log10 and 1.84log10, respectively. Studies both with CYP 3A4 inhibitors and inducers have demonstrated that Maraviroc will have manageable drug interactions when used in the setting of HIV patients receiving HAART. In summary, Maraviroc has potency, pharmacokinetic and toleration profiles that merit its further evaluation as a new therapy for patients with HIV/AIDS. from 2005 International Meeting of The Institute of Human Virology Baltimore, USA, 29 August – 2 September 2005

Recent advances in PDE4 inhibitors as immunoregulators and anti-inflammatory drugs.

The phosphodiesterases (PDEs) are responsible for the hydrolysis of intracellular cyclic adenosine and guanosine monophosphate (cAMP and cGMP, respectively). They are classified into 11 major families (PDE1-11) and the type 4 phosphodiesterase (PDE4) is a cAMP-specific enzyme localized in airway smooth muscle cells as well as in immune and inflammatory cells. The PDE4 activity is associated with a wide variety of diseases some of which have been related to an inflammatory state, (e.g. asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA)) while others have recently been connected to autoimmune pathology. Therefore, an intense effort toward the development of PDE4 inhibitors has been generated for the last decade. Unfortunately, the effects of prototype PDE4 inhibitors have been compromised by side effects such as nausea and emesis and the clinical use of those compounds is still limited. Several companies have focused on the design of a new generation of PDE4 inhibitors dissociating beneficial activity and adverse effects. This review highlights the recent data of the most advanced clinical candidates, the design and structure activity relationships of the recent structural series reported in the literature over the last two years, as well as recent advances in the multiple therapeutic indications of PDE4 inhibitors (a review with 375 references).

Drug-like properties and the causes of poor solubility and poor permeability

There are currently about 10 000 drug-like compounds. These are sparsely, rather than uniformly, distributed through chemistry space. True diversity does not exist in experimental combinatorial chemistry screening libraries. Absorption, distribution, metabolism, and excretion (ADME) and chemical reactivity-related toxicity is low, while biological receptor activity is higher dimensional in chemistry space, and this is partly explainable by evolutionary pressures on ADME to deal with endobiotics and exobiotics. ADME is hard to predict for large data sets because current ADME experimental screens are multi-mechanisms, and predictions get worse as more data accumulates. Currently, screening for biological receptor activity precedes or is concurrent with screening for properties related to “drugability.” In the future, “drugability” screening may precede biological receptor activity screening. The level of permeability or solubility needed for oral absorption is related to potency. The relative importance of poor solubility and poor permeability towards the problem of poor oral absorption depends on the research approach used for lead generation. A “rational drug design” approach as exemplified by Merck advanced clinical candidates leads to time-dependent higher molecular weight, higher H-bonding properties, unchanged lipophilicity, and, hence, poorer permeability. A high throughput screening (HTS)-based approach as exemplified by unpublished data on Pfizer (Groton, CT) early candidates leads to higher molecular weight, unchanged H-bonding properties, higher lipophilicity, and, hence, poorer aqueous solubility.