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. 2023 Sep 1:93:129430.
doi: 10.1016/j.bmcl.2023.129430. Epub 2023 Aug 4.

Discovery of 1,3-disubstituted pyrazole peripheral cannabinoid receptor partial agonists

George Amato  1 , Scott Runyon  1 , Vineetha Vasukuttan  1 , Ann M Decker  1 , Elaine A Gay  1 , Lucas Laudermilk  1 , Rangan Maitra  2
Affiliations

Discovery of 1,3-disubstituted pyrazole peripheral cannabinoid receptor partial agonists

George Amato et al. Bioorg Med Chem Lett. .

Abstract

Partial agonists of peripheral cannabinoid receptors (CBRs) have potential therapeutic applications in several medical conditions. However, (-)-trans-Δ9-tetrahydrocannabinol (THC), the principal active component of marijuana, which is a partial agonist of CB1 and CB2 penetrates the central nervous system (CNS) and produces adverse effects. Peripherally restricted partial agonists of CBRs, particularly of CB1, can be used to treat illnesses safely and effectively with a better therapeutic index. Here, we report on our efforts to synthesize pyrazole partial CBR agonists with peripheral selectivity, resulting in lead compound 40. This compound is a potent partial agonist of CB1 with ∼ 5-fold higher plasma biodistribution over brain and represents an early lead for optimization.

Keywords: Agonist; CB1; CB2; Cannabinoid; Compound; Peripheral.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1.
Figure 1.
BAY 59–3074, Literature Indazoles, and Pyrazole Targets.
Scheme 1.
Scheme 1.
Reagents and Conditions: (a) RBr, t-BuOK, THF, rt; (b) 2 N NaOH, Dioxane, 50 °C; (c) BOP, NEt3, MeCN, 50 °C.
Scheme 2.
Scheme 2.
Reagents and Conditions: (a) RBr, K2CO3, MeCN, 60 °C; (b) 2 N NaOH, THF, MeOH, rt; (c) (ClCO)2, DMF, CH2Cl2, rt, then RNH2, i-Pr2NEt, DMF, rt.
Scheme 3.
Scheme 3.
Reagents and Conditions: (a) RBr, K CO3, MeCN, 60°C; (b) 10% Pd/C, H2, EtOAc; (c) (ClCO)2,DMF, CH2Cl, then RNH2, i-Pr2NEt, DMF; (d) 2 N NaOH, THF, MeOH, rt; (e) 7 N NH3/MeOH, 70 °C.
Scheme 4.
Scheme 4.
Reagents and Conditions: (a) 10% Pd/C, H2, AcOH, EtOH; (b) TMSN3, Na Ascorbate, TBAF/THF, CuSO4.5H2O, t-BuOH, H2O, 80 °C; (c) Raney Ni, H2, MeOH; (d) Ac2O, Pyridine, CH2Cl2, rt.
Scheme 5.
Scheme 5.
Reagents and Conditions: (a) Conc. Sulfuric Acid, 80°C then MeOH, rt; (b) RCO2H, (ClCO)2, DMF, CH2Cl, rt, then i-Pr2 NEt, DMF, rt; (c) 7 N NH3/MeOH, 70 °C.
Scheme 6.
Scheme 6.
Reagents and Conditions: (a) (ClCO)2, DMF, CH2Cl2, rt, then RNH2, i-Pr2NEt, DMF, rt; (b) Me Acrylate, Pd(dppf)Cl, 9-BBN, K2CO3, THF, H2O, 80 °C; (c) 7 N NH3/MeOH, 70 °C (d) BnNH2, Pd2(dba)3, Tol-BINAP, t-BuOK, PhMe, 80°C; (e) 10% Pd/C, H2, EtOAc, rt; (f) Ac2O, Pyridine, CH2Cl2, rt; (g) MeSO2Cl, NEt3, CH2Cl2, rt; (h) Me2NCOCl or MeHNCOCl, Pyridine, DMAP, CH2Cl2, rt.
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