Design and synthesis of 1-aryl-5-anilinoindazoles as c-Jun N-terminal kinase inhibitors

Starting from pyrazole HTS hit (1), a series of 1-aryl-1H-indazoles have been synthesized as JNK3 inhibitors with moderate selectivity against JNK1. SAR studies led to the synthesis of 5r as double digital nanomolar JNK3 inhibitor with good in vivo exposure.     

COMPARATIVE ULTRASTRUCTURAL STUDIES OF SPERMATOGENESIS IN THE METZGERIALES (HEPATOPHYTA) II. THE BLEPHAROPLAST OF BLASIA PUSILLA

As in other hepatics, the young spermatid of Blasia pusilla contains a well-developed blepharoplast comprising a four-layered multilayered structure (MLS) and two overlying dimorphic basal bodies. The asymmetrical spline (S₁ or upper stratum of the MLS) numbers 20 or 21 microtubules (MTs) at its anterior tip and reduces to eight at the posterior limit of the lamellar strip (LS). Behind this the shank of the spline is five or six tubules in width over most of its length, approximately one revolution of the circumference of the gamete. The three-microtubule spline aperture underlies the anterior basal body and like those of most hepatics, it is closed at its anterior end. The asymmetrical LS (approx. 2.0 μm in length) is characterized by a right-hand posterior notch which lies below the spline aperture at the region of the cartwheel configuration of the anterior basal body (ABB). The staggered dimorphic basal bodies overlap for approximately one third of their lengths. Both lie parallel to the long axis of the spline. As in other hepatics, the ABB (1.2 μm in length) is subapical and comprises an anterior hub extension with progressive rearward additions of lateral, dorsal and ventral triplets. Over most of its length (2.1 μm) the longer posterior basal body (PBB) consists of a distinct central hub and three ventral triplets. Transition zones of both basal bodies contain stellate configurations into which the two central axonemal MTs frequently extend. The blepharoplast of Blasia shows several features in common with leafy, simple thalloid and complex thalloid liverworts. Compared with the few Metzgeriales observed thus far, the LS is less elongate and the basal bodies less staggered. Dimensions of basal body components and spline dimensions, however, are comparable to those of most leafy and thalloid hepatics. Striking similarities with the complex thalloid liverworts include a posterior notch in the LS and a spline aperture three MTs wide.     

Histoenzymology of the developing human basal ganglia

Summary Oxidative and hydrolytic enzyme activities are present in the anlage of the human basal ganglia as early as the second month of embryonic life, and acetylcholinesterase activity appears during the sixth month of pre-natal life.Clinical Research Fellow of the Medical Research Council. Presently in the Department of Neurology, Indiana University, Medical School.     

Chroman-3-amides as potent Rho kinase inhibitors

Inhibition of Rho kinase (ROCK) is an attractive strategy for the treatment of diseases such as hypertension, glaucoma, and cancer. Here we report chroman-3-amides as highly potent ROCK inhibitors with sufficient kinase selectivity, excellent cell activity, good microsomal stability, and desirable pharmacokinetic properties for study as potential therapeutic agents.