Synthesis and Biological Evaluation of N-((1-(4-(Sulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide Inhibitors of Glycine Transporter-1.

We previously disclosed the discovery of rationally designed N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1 (GlyT-1), represented by analogues 10 and 11. We describe herein further structure-activity relationship exploration of this series via an optimization strategy that primarily focused on the sulfonamide and benzamide appendages of the scaffold. These efforts led to the identification of advanced leads possessing a desirable balance of excellent in vitro GlyT-1 potency and selectivity, favorable ADME and in vitro pharmacological profiles, and suitable pharmacokinetic and safety characteristics.

Design, synthesis, and SAR of N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1.

The design, synthesis, and structure-activity relationships (SAR) of a series of N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1 (GlyT-1) are described. Optimization of the benzamide and central ring components of the core scaffold led to the identification of a GlyT-1 inhibitor that demonstrated in vivo activity in a rodent cerebral spinal fluid (CSF) glycine model.

(Z,2R,3R,4aR,7R,12aS)-2,3,7,8,12,12a-Hexahydro-2,3-dimethoxy-2,3,7-trimethyl-4aH-[1,4]dioxino[2,3-c]oxecin-5(11H)-one: a commensurate occupationally modulated structure revealing a condition for diffraction symmetry enhancement for non-parent reflections.

(Z,2R,3R,4aR,7R,12aS)-2,3,7,8,12,12a-Hexahydro-2,3-dimethoxy-2,3,7-trimethyl-4aH-[1,4]dioxino[2,3-c]oxecin-5(11H)-one (C16H26O6) crystallizes in the space group P3(1) and approximates the conditions necessary for diffraction symmetry enhancement without twinning for the h - k not = 3N reflections. The structure may be described as an occupancy modulation of a 1:1 disordered P3(1)21 parent structure with Z = 3 that would only contribute to the h - k = 3N reflections. The crystal studied was a 0.

A chemoenzymatic total synthesis of the undecenolide (-)-cladospolide B via a mid-stage ring-closing metathesis and a late-stage photo-rearrangement of the E-isomer.

A sixteen-step synthesis of the twelve-membered macrolide (-)-cladospolide B(2) from the microbially-derived cis-1,2-dihydrocatechol 5 is described. Pivotal steps include the ring-closing metathesis (RCM) of diene 12 to give the ten-membered lactone 13 together with small amounts of the head-to-tail and head-to-head dimers 14 and 15, respectively. The saturated lactol 19 derived from compounds 13 and 14 readily participates in a Wadsworth-Horner-Emmons reaction to give the E-configured alpha,beta-unsaturated ester 20.

A chemoenzymatic total synthesis of the phytotoxic undecenolide (-)-cladospolide A.

An eleven-step synthesis of the title compound (1) from biocatalytically-derived and enantiomerically pure 'building blocks' alcohol (R)-(-)-9 and ester 13 is described. Attempts to construct the twelve-membered lactone ring of cladospolide A in a direct manner by using a ring-closing metathesis (RCM) reaction failed. However, a ten-membered lactone 19, could be constructed by such means and this was then subject to a two-carbon homologation sequence involving, inter alia, Wadsworth-Horner-Emmons and Yamaguchi lactonisation reactions in the closing stages of the synthesis.