RESUMO
An efficient large-scale synthesis of acid 1, a penultimate precursor to the HCV NS5A inhibitor BMS-986097, along with the final API step are described. Three routes were devised for the synthesis of 1 at the various stages of the program. The third generation route, the one that proved scalable and is the main subject of this paper, features a one-step Michael addition of t-butyl 2-((diphenylmethylene)amino)acetate (24) to (E)-benzyl 4-(1-hydroxycyclopropyl)but-2-enoate (28) followed by cyclization and chiral separation to form 27c, the core skeleton of cap piece 1. The epimerization and chiral resolution of 27c followed by further synthetic manipulations involving the carbamate formation, lactone reduction and cyclization, afforded cyclopropyl pyran 1. A detailed study of diphenylmethane deprotection via acid hydrolysis as well as a key lactone to tetrahydropyran conversion, in order to avoid a side reaction that afforded an alternative cyclization product, are discussed. This synthesis was applied to the preparation of more than 100 g of the final API BMS-986097 for toxicology studies.
Assuntos
Antivirais/síntese química , Glicina/análogos & derivados , Imidazóis/síntese química , Piranos/farmacologia , Pirrolidinas/síntese química , Compostos de Espiro/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Antivirais/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Estrutura Molecular , Piranos/síntese química , Piranos/química , Pirrolidinas/química , Pirrolidinas/farmacologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Proteínas não Estruturais Virais/metabolismoRESUMO
BMS-791325 is an allosteric inhibitor that binds to thumb site 1 of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase. BMS-791325 inhibits recombinant NS5B proteins from HCV genotypes 1, 3, 4, and 5 at 50% inhibitory concentrations (IC50) below 28 nM. In cell culture, BMS-791325 inhibited replication of HCV subgenomic replicons representing genotypes 1a and 1b at 50% effective concentrations (EC50s) of 3 nM and 6 nM, respectively, with similar (3 to 18 nM) values for genotypes 3a, 4a, and 5a. Potency against genotype 6a showed more variability (9 to 125 nM), and activity was weaker against genotype 2 (EC50, 87 to 925 nM). Specificity was demonstrated by the absence of activity (EC50s of >4 µM) against a panel of mammalian viruses, and cytotoxic concentrations (50%) were >3,000-fold above the HCV EC50. Resistance substitutions selected by BMS-791325 in genotype 1 replicons mostly mapped to a single site, NS5B amino acid 495 (P495A/S/L/T). Additive or synergistic activity was observed in combination studies using BMS-791325 with alfa interferon plus ribavirin, inhibitors of NS3 protease or NS5A, and other classes of NS5B inhibitor (palm site 2-binding or nucleoside analogs). Plasma and liver exposures in vivo in several animal species indicated that BMS-791325 has a hepatotropic disposition (liver-to-plasma ratios ranging from 1.6- to 60-fold across species). Twenty-four hours postdose, liver exposures across all species tested were ≥ 10-fold above the inhibitor EC50s observed with HCV genotype 1 replicons. These findings support the evaluation of BMS-791325 in combination regimens for the treatment of HCV. Phase 3 studies are ongoing.
Assuntos
Antivirais/farmacologia , Benzazepinas/farmacologia , Hepacivirus/enzimologia , Indóis/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Regulação Alostérica , Animais , Antivirais/química , Benzazepinas/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Cães , Farmacorresistência Viral , Quimioterapia Combinada , Genótipo , Hepacivirus/efeitos dos fármacos , Humanos , Indóis/química , Interferon-alfa/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Replicon/efeitos dos fármacos , Ribavirina/farmacologia , Células VeroRESUMO
Efforts investigating spatially comparative alternates of the ethylene-bridged piperazine in BMS-791325 that would offer a maintained or improved virologic and pharmacokinetic profile have been multifaceted. One foray involved the utilization of various octahydropyrrolo[3,4-c]pyrrole propellanes. Many of the propellane analogs described in this work exhibited better than targeted potency (less than 20 nM). Additionally, improved exposure in rats was achieved through the employment of two newly invented and now readily accessible carbon bridged propellanes as compared to their heteroatom bridged analogs.
Assuntos
Antivirais/química , Antivirais/farmacocinética , Hepacivirus , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Benzazepinas/química , Indóis/química , Estrutura Molecular , RatosRESUMO
A neuromechanical simulation of the cockroach Blaberus discoidalis was developed to explore changes in locomotion when the animal transitions from walking straight to turning. The simulation was based upon the biological data taken from three sources. Neural circuitry was adapted from the extensive literature primarily obtained from the studies of neural connections within thoracic ganglia of stick insect and adapted to cockroach. The 3D joint kinematic data on straight, forward walking for cockroach were taken from a paper that describes these movements in all joints simultaneously as the cockroach walked on an oiled-plate tether (Bender et al. in PloS one 5(10):1-15, 2010b). Joint kinematics for turning were only available for some leg joints (Mu and Ritzmann in J Comp Physiol A Neuroethol Sens Neural Behav Physiol 191(11):1037-54, 2005) and thus had to be obtained using the methods that were applied for straight walking by Bender et al. (PloS one 5(10):1-15, 2010b). Once walking, inside turning, and outside turning were characterized, phase and amplitude changes for each joint of each leg were quantified. Apparent reflex reversals and joint activity changes were used to modify sensory coupling pathways between the CPG at each joint of the simulation. Oiled-plate experiments in simulation produced tarsus trajectories in stance similar to those seen in the animal. Simulations including forces that would be experienced if the insect was walking freely (i.e., weight support and friction) again produced similar results. These data were not considered during the design of the simulation, suggesting that the simulation captures some key underlying the principles of walking, turning, and transitioning in the cockroach. In addition, since the nervous system was modeled with realistic neuron models, biologically plausible reflex reversals are simulated, motivating future neurobiological research.
Assuntos
Baratas/fisiologia , Estimulação Elétrica/métodos , Locomoção/fisiologia , Modelos Neurológicos , Redes Neurais de Computação , Animais , Fenômenos BiomecânicosRESUMO
A series of HIV-1 attachment inhibitors containing a 4,6-diazaindole core were examined in an effort to identify a compound which improved upon the potency and oral exposure of BMS-488043 (2). BMS-488043 (2) is a 6-azaindole-based HIV-1 attachment inhibitor which established proof-of-concept for this mechanism in human clinical studies but required high doses and concomitant administration of a high fat meal to achieve efficacious exposures. Based on previous studies in indole and azaindole scaffolds, SAR investigation was concentrated around the key 7-position in the 4,6-diazaindole series and led to the discovery of molecules with 5- to 20-fold increases in potency and three- to seven-fold increases in exposure over 2 in a rat PK studies.
Assuntos
Fármacos Anti-HIV/química , Compostos Aza/química , HIV-1/metabolismo , Indóis/química , Administração Oral , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Avaliação Pré-Clínica de Medicamentos , HIV-1/efeitos dos fármacos , Meia-Vida , Humanos , Piperazinas/química , Piperazinas/farmacocinética , Ácido Pirúvico , Ratos , Relação Estrutura-Atividade , Ligação Viral/efeitos dos fármacosRESUMO
A series of 4-azaindole oxoacetic acid piperazine benzamides was synthesized and evaluated in an effort to identify an oral HIV-1 attachment inhibitor with the potential to improve upon the pre-clinical profile of BMS-378806 (7), an initial clinical compound. Modifications at the 7-position of the 4-azaindole core modulated potency significantly and SAR showed that certain compounds with a 5-membered ring heteroaryl group at that position were the most potent. Four of the compounds with the best profiles were evaluated in a rat pharmacokinetic model and all had superior oral bioavailability and lower clearance when compared with 7.
Assuntos
Fármacos Anti-HIV/química , HIV-1/metabolismo , Indóis/química , Administração Oral , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Disponibilidade Biológica , Avaliação Pré-Clínica de Medicamentos , HIV-1/efeitos dos fármacos , Meia-Vida , Humanos , Piperazinas/química , Piperazinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Ligação Viral/efeitos dos fármacosRESUMO
Long-acting (LA) human immunodeficiency virus-1 (HIV-1) antiretroviral therapy characterized by a ≥1 month dosing interval offers significant advantages over daily oral therapy. However, the criteria for compounds that enter clinical development are high. Exceptional potency and low plasma clearance are required to meet dose size requirements; excellent chemical stability and/or crystalline form stability is required to meet formulation requirements, and new antivirals in HIV-1 therapy need to be largely free of side effects and drug-drug interactions. In view of these challenges, the discovery that capsid inhibitors comprising a quinazolinone core tolerate a wide range of structural modifications while maintaining picomolar potency against HIV-1 infection in vitro, are assembled efficiently in a multi-component reaction, and can be isolated in a stereochemically pure form is reported herein. The detailed characterization of a prototypical compound, GSK878, is presented, including an X-ray co-crystal structure and subcutaneous and intramuscular pharmacokinetic data in rats and dogs.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Humanos , Ratos , Animais , Cães , Capsídeo , Proteínas do Capsídeo , Quinazolinonas/farmacologia , Quinazolinonas/uso terapêutico , Fármacos Anti-HIV/farmacocinética , Infecções por HIV/tratamento farmacológicoRESUMO
BACKGROUND: Reactive risk assessments (RRAs) such as incident reporting and root cause analysis (RCA), as well as proactive risk assessments (PRAs) such as failure mode and effects analysis, are generally conducted independently in health care. Literature promotes combining risk assessment techniques. This concept builds on previous methodologies and presents an innovative, scalable, and generalizable risk assessment methodology. METHODS: A Combined Proactive Risk Assessment (CPRA) technique entails combining incident reports (RRAs), combining proactive risk assessments (PRAs), and merging components of PRA and RRA. Using specific keywords, this technique aligns patient safety reporting data with process steps and failure modes to assess risk within any of the process steps. This technique was tested by using PRAs from several Veterans Health Administration (VHA) facilities and national patient safety data from the VHA National Center for Patient Safety's database. Reported events and RCAs related to the outpatient blood draw process were used for this illustration. Repeatability was determined by independently applying the technique to two years of data and auditing results. RESULTS: Aggregating PRAs from multiple facilities identified 220% more failure modes; and integrating incident reports into PRA identified 310% more failure modes than the single facility average. Overlaying safety reports onto a comprehensive process flow diagram revealed that 85.8% of events occurred in three of seven process steps. Accuracy of this technique was generally above 85%. CONCLUSION: This technique is promising for identifying vulnerable points in health care processes or to compliment a traditional PRA. Single PRAs are less likely to identify all potential failures or focus on the most hazardous process steps. This technique may aid in assessing key health care processes at an enterprise level.
Assuntos
Segurança do Paciente , Análise de Causa Fundamental , Atenção à Saúde , Instalações de Saúde , Humanos , Medição de RiscoRESUMO
Earlier observations had suggested that cockroaches might show multiple patterns of leg coordination, or gaits, but these were not followed by detailed behavioral or kinematic measurements that would allow a definite conclusion. We measured the walking speeds of cockroaches exploring a large arena and found that the body movements tended to cluster at one of two preferred speeds, either very slow (<10 cm s(-1)) or fairly fast (â¼30 cm s(-1)). To highlight the neural control of walking leg movements, we experimentally reduced the mechanical coupling among the various legs by tethering the animals and allowing them to walk in place on a lightly oiled glass plate. Under these conditions, the rate of stepping was bimodal, clustering at fast and slow speeds. We next used high-speed videos to extract three-dimensional limb and joint kinematics for each segment of all six legs. The angular excursions and three-dimensional motions of the leg joints over the course of a stride were variable, but had different distributions in each gait. The change in gait occurs at a Froude number of â¼0.4, a speed scale at which a wide variety of animals show a transition between walking and trotting. We conclude that cockroaches do have multiple gaits, with corresponding implications for the collection and interpretation of data on the neural control of locomotion.
Assuntos
Baratas/fisiologia , Animais , Fenômenos Biomecânicos , Marcha , Gravação em Vídeo , CaminhadaRESUMO
The hepatitis C virus (HCV) NS5B replicase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Inspired by the overlay of bound structures of three structurally distinct NS5B palm site allosteric inhibitors, the high-throughput screening hit anthranilic acid 4, the known benzofuran analogue 5, and the benzothiadiazine derivative 6, an optimization process utilizing the simple benzofuran template 7 as a starting point for a fragment growing approach was pursued. A delicate balance of molecular properties achieved via disciplined lipophilicity changes was essential to achieve both high affinity binding and a stringent targeted absorption, distribution, metabolism, and excretion profile. These efforts led to the discovery of BMS-929075 (37), which maintained ligand efficiency relative to early leads, demonstrated efficacy in a triple combination regimen in HCV replicon cells, and exhibited consistently high oral bioavailability and pharmacokinetic parameters across preclinical animal species. The human PK properties from the Phase I clinical studies of 37 were better than anticipated and suggest promising potential for QD administration.
Assuntos
Antivirais/farmacologia , Antivirais/farmacocinética , Benzofuranos/farmacologia , Benzofuranos/farmacocinética , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Proteínas não Estruturais Virais/antagonistas & inibidores , Regulação Alostérica/efeitos dos fármacos , Sítio Alostérico/efeitos dos fármacos , Animais , Antivirais/química , Benzofuranos/química , Cães , Descoberta de Drogas , Haplorrinos , Hepatite C/virologia , Humanos , Masculino , Simulação de Acoplamento Molecular , Ratos , Ratos Sprague-Dawley , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismoRESUMO
Animals such as cockroaches depend on exploration of unknown environments, and their strategies may inspire robotic approaches. We have previously shown that cockroach behavior, with respect to shelters and the walls of an otherwise empty arena, can be captured with a stochastic state-based algorithm. We call this algorithm RAMBLER, randomized algorithm mimicking biased lone exploration in roaches. In this work, we verified and extended this model by adding a barrier in the previously used arena and conducted more cockroach experiments. In two arena configurations, our simulated model's path length distribution was similar to the experimental distribution (mean experimental path length 3.4 and 3.2 m, mean simulated path length 3.9 and 3.3 m). By analyzing cockroach behavior before, along, and at the end of the barrier, we have generalized RAMBLER to address arbitrarily complex 2D mazes. For biology, this is an abstract behavioral model of a decision-making process in the cockroach brain. For robotics, this is a strategy that may improve exploration for goals, especially in unpredictable environments with non-convex obstacles. Generally, cockroach behavior seems to recommend variability in the absence of planning, and following paths defined by walls.
Assuntos
Biomimética/métodos , Baratas/fisiologia , Comportamento Exploratório/fisiologia , Modelos Biológicos , Robótica/métodos , Tato/fisiologia , Animais , Comportamento Animal/fisiologia , Simulação por Computador , Abrigo para Animais , Comportamento Espacial/fisiologiaRESUMO
The behavior of individuals determines the strength and outcome of ecological interactions, which drive population, community, and ecosystem organization. Bio-logging, such as telemetry and animal-borne imaging, provides essential individual viewpoints, tracks, and life histories, but requires capture of individuals and is often impractical to scale. Recent developments in automated image-based tracking offers opportunities to remotely quantify and understand individual behavior at scales and resolutions not previously possible, providing an essential supplement to other tracking methodologies in ecology. Automated image-based tracking should continue to advance the field of ecology by enabling better understanding of the linkages between individual and higher-level ecological processes, via high-throughput quantitative analysis of complex ecological patterns and processes across scales, including analysis of environmental drivers.
Assuntos
Distribuição Animal , Comportamento Animal , Ecologia/tendências , Telemetria , AnimaisRESUMO
Lead inhibitors that target the function of the hepatitis C virus (HCV) nonstructural 5A (NS5A) protein have been identified by phenotypic screening campaigns using HCV subgenomic replicons. The demonstration of antiviral activity in HCV-infected subjects by the HCV NS5A replication complex inhibitor (RCI) daclatasvir (1) spawned considerable interest in this mechanistic approach. In this Perspective, we summarize the medicinal chemistry studies that led to the discovery of 1 and other chemotypes for which resistance maps to the NS5A protein and provide synopses of the profiles of many of the compounds currently in clinical trials. We also summarize what is currently known about the NS5A protein and the studies using NS5A RCIs and labeled analogues that are helping to illuminate aspects of both protein function and inhibitor interaction. We conclude with a synopsis of the results of notable clinical trials with HCV NS5A RCIs.
Assuntos
Descoberta de Drogas , Hepacivirus/metabolismo , Proteínas não Estruturais Virais/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Hepacivirus/fisiologia , Proteínas não Estruturais Virais/metabolismoRESUMO
Described herein are structure-activity relationship studies that resulted in the optimization of the activity of members of a class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors. Subsequent iterations of analogue design and syntheses successfully addressed off-target activities, most notably human pregnane X receptor (hPXR) transactivation, and led to significant improvements in the physicochemical properties of lead compounds. Those analogues exhibiting improved solubility and membrane permeability were shown to have notably enhanced pharmacokinetic profiles. Additionally, a series of alkyl bridged piperazine carboxamides was identified as being of particular interest, and from which the compound BMS-791325 (2) was found to have distinguishing antiviral, safety, and pharmacokinetic properties that resulted in its selection for clinical evaluation.
Assuntos
Antivirais/farmacologia , Benzazepinas/farmacologia , Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Regulação Alostérica , Animais , Antivirais/química , Antivirais/farmacocinética , Benzazepinas/química , Benzazepinas/farmacocinética , Cães , Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Indóis/química , Indóis/farmacocinética , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Modelos Moleculares , Ratos , Relação Estrutura-AtividadeRESUMO
What are the fundamental constraints on the precision and accuracy with which nervous systems can process information? One constraint must reflect the intrinsic "noisiness" of the mechanisms that transmit information between nerve cells. Most neurons transmit information through the probabilistic generation and propagation of spikes along axons, and recent modeling studies suggest that noise from spike propagation might pose a significant constraint on the rate at which information could be transmitted between neurons. However, the magnitude and functional significance of this noise source in actual cells remains poorly understood. We measured variability in conduction time along the axons of identified neurons in the cercal sensory system of the cricket Acheta domesticus, and used information theory to calculate the effects of this variability on sensory coding. We found that the variability in spike propagation speed is not large enough to constrain the accuracy of neural encoding in this system.
Assuntos
Axônios/fisiologia , Gryllidae/fisiologia , Teoria da Informação , Interneurônios/fisiologia , Modelos Neurológicos , Condução Nervosa/fisiologia , Potenciais de Ação/fisiologia , Animais , Feminino , Dinâmica não Linear , Estimulação Física , Processos EstocásticosRESUMO
Animals must routinely deal with barriers as they move through their natural environment. These challenges require directed changes in leg movements and posture performed in the context of ever changing internal and external conditions. In particular, cockroaches use a combination of tactile and visual information to evaluate objects in their path in order to effectively guide their movements in complex terrain. When encountering a large block, the insect uses its antennae to evaluate the object's height then rears upward accordingly before climbing. A shelf presents a choice between climbing and tunneling that depends on how the antennae strike the shelf; tapping from above yields climbing, while tapping from below causes tunneling. However, ambient light conditions detected by the ocelli can bias that decision. Similarly, in a T-maze turning is determined by antennal contact but influenced by visual cues. These multi-sensory behaviors led us to look at the central complex as a center for sensori-motor integration within the insect brain. Visual and antennal tactile cues are processed within the central complex and, in tethered preparations, several central complex units changed firing rates in tandem with or prior to altered step frequency or turning, while stimulation through the implanted electrodes evoked these same behavioral changes. To further test for a central complex role in these decisions, we examined behavioral effects of brain lesions. Electrolytic lesions in restricted regions of the central complex generated site specific behavioral deficits. Similar changes were also found in reversible effects of procaine injections in the brain. Finally, we are examining these kinds of decisions made in a large arena that more closely matches the conditions under which cockroaches forage. Overall, our studies suggest that CC circuits may indeed influence the descending commands associated with navigational decisions, thereby making them more context dependent.
RESUMO
BMS-663749, a phosphonooxymethyl prodrug 4 of the HIV-1 attachment inhibitor 2-(4-benzoyl-1-piperazinyl)-1-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoethanone (BMS-488043) (2) was prepared and profiled in a variety of preclinical in vitro and in vivo models designed to assess its ability to deliver parent drug following oral administration. The data showed that prodrug 4 had excellent potential to significantly reduce dissolution rate-limited absorption following oral dosing in humans. Clinical studies in normal healthy subjects confirmed the potential of 4, revealing that the prodrug significantly increased both the AUC and C(max) of 2 compared to a solid capsule formulation containing the parent drug upon dose escalation. These data provided guidance for further efforts to obtain an effective HIV-1 attachment inhibitor.
Assuntos
Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Organofosfatos/farmacologia , Piperazinas/farmacologia , Pró-Fármacos/farmacologia , Ligação Viral/efeitos dos fármacos , Administração Oral , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Gorduras na Dieta/administração & dosagem , Cães , Interações Alimento-Droga , HIV-1/fisiologia , Haplorrinos , Humanos , Indóis , Organofosfatos/química , Organofosfatos/farmacocinética , Piperazinas/química , Piperazinas/farmacocinética , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Ácido Pirúvico , Ratos , SolubilidadeRESUMO
High-speed video can provide fine-scaled analysis of animal behavior. However, extracting behavioral data from video sequences is a time-consuming, tedious, subjective task. These issues are exacerbated where accurate behavioral descriptions require analysis of multiple points in three dimensions. We describe a new computer program written to assist a user in simultaneously extracting three-dimensional kinematics of multiple points on each of an insect's six legs. Digital video of a walking cockroach was collected in grayscale at 500 fps from two synchronized, calibrated cameras. We improved the legs' visibility by painting white dots on the joints, similar to techniques used for digitizing human motion. Compared to manual digitization of 26 points on the legs over a single, 8-second bout of walking (or 106,496 individual 3D points), our software achieved approximately 90% of the accuracy with 10% of the labor. Our experimental design reduced the complexity of the tracking problem by tethering the insect and allowing it to walk in place on a lightly oiled glass surface, but in principle, the algorithms implemented are extensible to free walking. Our software is free and open-source, written in the free language Python and including a graphical user interface for configuration and control. We encourage collaborative enhancements to make this tool both better and widely utilized.
Assuntos
Baratas/fisiologia , Computadores , Animais , Fenômenos Biomecânicos , Calibragem , Baratas/anatomia & histologia , FemininoRESUMO
Animals negotiating complex natural terrain must consider cues around them and alter movement parameters accordingly. In the arthropod brain, the central complex (CC) receives bilateral sensory relays and sits immediately upstream of premotor areas, suggesting that it may be involved in the context-dependent control of behavior. In previous studies, CC neurons in various insects responded to visual, chemical, and mechanical stimuli, and genetic or physical lesions affected locomotor behaviors. Additionally, electrical stimulation of the CC led to malformed chirping movements by crickets, and pharmacological stimulation evoked stridulation in grasshoppers, but no more precise relationship has been documented between neural activity in the CC and movements in a behaving animal. We performed tetrode recordings from the CC of cockroaches walking in place on a slippery surface. Neural activity in the CC was strongly correlated with, and in some cases predictive of, stepping frequency. Electrical stimulation of these areas also evoked or modified walking. Many of the same neural units responded to tactile antennal stimulation while the animal was standing still but became unresponsive during walking. Therefore, these CC units are unlikely to be reporting only sensory signals, but their activity may be directing changes in locomotion based on sensory inputs.