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.

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. Representative analogue (+)-67 exhibited robust in vivo activity in the cerebral spinal fluid glycine biomarker model in both rodents and nonhuman primates. Furthermore, rodent microdialysis experiments also demonstrated that oral administration of (+)-67 significantly elevated extracellular glycine levels within the medial prefrontal cortex (mPFC).

(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 0.717 (2):0.283 twin, but also had a stacking fault that on average caused the (1 - p(j)):p(j) population ratio for the alternative orientations of ordered columns along the three non-equivalent screw axes (j = 1, 2 or 3) of P3(1) to be describable by p1 = 0.068 (3), p2 = p3 = 0.960 (3). The effect of these stacking faults could be simulated using global parameters that modify an ordered prototype structure. The structure reveals that the ten-membered lactone ring incorporates a Z-configured double bond and that the methoxy-substituted stereogenic centers created during a trans-diol protection step each possess the R-configuration.

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. This last compound is then converted, through application of a Yamaguchi lactonisation reaction on the derived acid 22, into the macrolide 23 which, upon removal of the bis-acetal protecting group, affords compound 24, the E-isomer of target 2. Irradiation of a benzene solution of compound 24 results in its partial photoisomerisation to (-)-cladospolide B(2).

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. The impact of substituent stereochemistries and protecting groups on the RCM reaction leading to various ten-membered lactones is also described.