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Shinichi Niwa

Publications and source records attributed to Shinichi Niwa.

8 recordsLinked to original sources
PubMed2006

Discovery of a piperidine-4-carboxamide CCR5 antagonist (TAK-220) with highly potent Anti-HIV-1 activity.

We incorporated various polar groups into previously described piperidine-4-carboxamide CCR5 antagonists to improve their metabolic stability in human hepatic microsomes. Introducing a carbamoyl group into the phenyl ring of the 4-benzylpiperidine moiety afforded the less lipophilic compound 5f, which possessed both high metabolic stability and good inhibitory activity of HIV-1 envelope-mediated membrane fusion (IC(50) = 5.8 nM). Further optimization to increase potency led to the discovery of 1-acetyl-N-{3-[4-(4-carbamoylbenzyl)piperidin-1-yl]propyl}-N-(3-chloro-4-methylphenyl)piperidine-4-carboxamide (5m, TAK-220), which showed high CCR5 binding affinity (IC(50) = 3.5 nM) and potent inhibition of membrane fusion (IC(50) = 0.42 nM), as well as good metabolic stability. Compound 5m strongly inhibited the replication of CCR5-using HIV-1 clinical isolates in human peripheral blood mononuclear cells (mean EC(50) = 1.1 nM, EC(90) = 13 nM) and exhibited a good pharmacokinetic profile in monkeys (BA = 29%). This compound has been chosen as a clinical candidate for further development.

Animals↗
PubMed2005

Disorganization of semantic memory underlies alogia in schizophrenia: an analysis of verbal fluency performance in Japanese subjects.

Patients with schizophrenia exhibit impaired semantic memory as well as deficits in a wide range of language-related functions, such as verbal fluency, comprehension and production of complex sentences. Since language and memory disturbances may underlie some of the psychotic symptoms of schizophrenia, the present study investigated the specific association between alogia (i.e. poverty of speech, poverty of content of speech, blocking, and increased latency of response) and semantic memory organization using the category fluency task (CFT) as a measure of verbal fluency. Thirty-eight patients with schizophrenia and an equal number of normal controls entered the study. Semantic structure was derived from multidimensional scaling analysis using sequential word outputs from the CFT. Patients with schizophrenia revealed disorganized semantic structure (e.g. irregular association of category members) compared with controls, consistent with previous reports. The patients were then divided into two groups, i.e. alogia- and non-alogia subjects, based on the Alogia scores from the Scale for the Assessment of Negative Symptoms (SANS). The symptom-based analysis showed that the semantic structure for the alogia group (Alogia score < or =2) was more disorganized than that for the non-alogia group (Alogia score <1) although the number of words produced did not differ between the two groups. The results of cluster analysis revealed the presence of bizarre coherence specifically in the alogia group. These results indicate that semantic memory disorganization may contribute to the symptom of alogia in schizophrenia. In addition, this is one of the few studies that examined verbal fluency in Japanese patients with schizophrenia and suggest that the language abnormalities in schizophrenia are universal.

Adult↗
PubMed2004

Effect of orthography on the verbal fluency performance in schizophrenia: examination using Japanese patients.

Letter fluency performance is less impaired than the category fluency performance in alphabetical-language speakers with schizophrenia. The purpose of this study was to determine whether the same pattern in the performance on the two verbal fluency tasks exists in subjects using a non-alphabetical language. In the Japanese orthography, there is one-to-one correspondence between sound (syllable) and graphemes ("kana" script), in contrast to one-to-many associations in alphabetical languages (e.g. English, French). The category fluency task (ANIMAL, FRUIT) and the letter fluency task ("KA", "TA" in "kana" script) were administered on 38 patients with schizophrenia and the equal number of normal controls. In order to examine the influence of psychotic symptoms on the verbal fluency performance, the Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS) were administered. The patients performed significantly worse both in the letter- and category fluency tasks compared with control subjects. However, performance on the letter fluency task and category fluency task was similarly impaired in Japanese patients with schizophrenia, unlike the results in previous studies with alphabetical-language speakers. On the other hand, Alogia symptoms, as assessed by SANS, was a significant predictive variable in the regression model for the category fluency task score (ANIMAL), whereas the factor of the other domains of negative symptoms as a whole was a significant predictive variable in the model for the letter fluency task score (TA), which confirmed the findings in previous studies with alphabetical-language subjects. These results suggest that the pattern of impairment in the verbal fluency performance in schizophrenia is dependent on the specific language systems used by the patients although the degradation of the verbal fluency performance is influenced by some types of negative symptoms irrespective of the language system.

Adult↗