1-Sulfonyl-4-acylpiperazines as Selective Cannabinoid-1 Receptor (CB1R) Inverse Agonists for the Treatment of Obesity

Abstract

A novel series of 1-sulfonyl-4-acylpiperazines as selective cannabinoid-1 receptor (CB1R) inverse agonists was discovered through high throughput screening (HTS) and medicinal chemistry lead optimization. Potency and in vivo properties were systematically optimized to afford orally bioavailable, highly efficacious, and selective CB1R inverse agonists that caused food intake suppression and body weight reduction in diet-induced obese rats and dogs. It was found that the receptor binding assay predicted in vivo efficacy better than functional antagonist/inverse agonist activities. This observation expedited the structure-activity relationship (SAR) analysis and may have implications beyond the series of compounds presented herein.

Thia‐Michael Addition: An Emerging Strategy in Organic Synthesis

“…Over the past decade, sulfonamides have attracted significant attention, owing to their extensive biological applications, such as in HIV-integrasei nhibitors, carbonic anhydrase inhibitors, Cannabinoid-1r eceptor agonists, MMP inhibitors, and HIV-1 protease inhibitors. [76][77][78][79][80] Therefore, substantial time and effort have been expended to develop efficient and environmentally benigns ynthetic methods for cyclic sulfonamides.I n this direction, in 2015, the Zhou group synthesized eight-membered sulfonamides 54 from at hia-Michael addition reaction of NaSH to vinyl sulfones 53 in water under mild conditions (Scheme 41). First, the thia-Michael addition reaction took place to afford intermediate I.Next, intramolecular nucleophilic attack of the SH group on the terminal epoxide carbon atom, followed by ring-opening, furnished cyclic sulfonamides 54 in moderate-to-highy ields.…”

Peptidic Inhibitors and a Fluorescent Probe for the Selective Inhibition and Labelling of Factor XIIIa Transglutaminase

“…The supporting information containing detailed description of the synthesis [ 42 , 51 , 53 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 ], characterization, and supplementary figures can be downloaded at: , Scheme S1: Synthesis of Fmoc-AA(Acrylamide)-OH monomers 5-8 required for the production of acrylamide-bearing peptidic inhibitors; Scheme S2: Synthesis of Fmoc-D-Asp(OtBu)-OH 9 required for the production of acrylamideand α-chloroacetamide-bearing peptidic inhibitors; Scheme S3: Synthesis of acrylamide-bearing peptidic inhibitors 11–14; Scheme S4: Synthesis of Fmoc-AA(Alloc)-OH monomers 17–19 required for the production of αchloroacetamide-bearing peptidic inhibitors; Scheme S5: Synthesis of α-chloroacetamide-bearing peptidic inhibitors 20–23; Scheme S6: Synthesis of Boc-Glu(MA)-OH 28 required for the production of ZED1301; Scheme S7: Synthesis of Boc-AA(MA)-OH monomers 33 and 37 required for the production of α,β-unsaturated ester-bearing peptidic inhibitors; Scheme S8: Synthesis of Ac-D-Asp(OtBu)-OH 38 required for the production of α,β-unsaturated ester-bearing peptidic inhibitors; Scheme S9: Synthesis of α,β-unsaturated ester-bearing peptidic inhibitors 45–47; Scheme S10: General synthetic scheme to arrive at L-Dap key intermediate for small molecule inhibitors 66–68; Scheme S11: Synthetic scheme to arrive at malonyl inhibitors 71 and 72; Scheme S12: Synthetic scheme to arrive at cyclopropyl inhibitor 74 through the methyl ester 73; Scheme S13: Synthetic scheme to generate succinyl inhibitors 75–77; Scheme S14: Synthetic scheme to synthesize sulfonyl inhibitor 79; Scheme S15: General synthetic scheme to arrive at D-Dap scaffold key intermediate 83; Scheme S16: Synthetic scheme to generate D-Dap succinyl inhibitor 84; Scheme S17: General synthetic scheme to generate α,β-unsaturated warhead key intermediate 86; Scheme S18: Synthetic scheme to produce α,β-unsaturated succinyl inhibitor 87; Scheme S19: Synthetic scheme to produce α,β-unsaturated phthalyl inhibitor 88; Scheme S20: Synthesis of Rhodamine-B-ZED1301 fluorescent probe 93 (KM93); Scheme S21: Synthesis of Fmoc-6AH-OH 89 required for the production of fluorescent probe 93 (KM93); Figure S1: Fluorescence-time curve of the spike experiment performed with inhibitor 47 to confirm the reversibility of FXIIIa inhibition. Additional A101 substrate was added to the reactions corresponding to the positive control with no inhibitor (+ve), the negative control with no enzyme (−ve), and all 4 inhibitor concentrations (1, 2, 5, and 10 μM) after the initial plateaus in fluorescence had been reached.…”

Parallel Syntheses of Eight-Membered Ring Sultams via Two Cascade Reactions in Water

“…Figure presents several sulfonamide derivatives which display various potent biological activities. These include a H4 receptor inverse agonist, a carbonic anhydrase inhibitor, a cannabinoid-1 receptor (CB1R) inverse agonist for the treatment of obesity, an MMP inhibitor, an HIV-1 protease inhibitor, or an antagonist for the EP1 receptor . Here, we’ve developed two efficient cascade ring-forming sultam synthesis reactions which were carried out in water.…”