Synthesis of galmic: a nonpeptide galanin receptor agonist

Abstract

Galanin is a neuropeptide with a wide variety of biological functions. Few nonpeptide ligands, capable of activating galanin receptors, are available today. Based on known pharmacophores of galanin and the tripeptidomimetic galnon, a combinatorial library was formulated, synthesized, and screened against the galanin receptor. An active compound, galmic, was identified and tested in vitro and in vivo for its affinity and efficacy at galanin receptors. The present work describes the total synthesis of galmic, the synthesis of its oxazole precursors, the coupling of the building blocks into a linear trimer, and the macrolactamization reaction.

Fig. 1.

Nonpeptide ligands of the galanin receptor.

Fig. 2.

Synthesis of the libraries.

Fig. 3.

Retrosynthetic disconnection of galmic.

Fig. 4.

Hydrolysis and decarboxylation of 9.

Fig. 5.

Synthesis of the oxazole monomers. Reagents and conditions: (i) i-PrOH, N,N-dicyclohexylcarbodiimide, DMAP, DCM, RT, overnight (84%); (ii) LiOH, tetrahydrofuran/H₂O, RT, 30 min (98%); (iii) cyclohexylmethylamine 2, diphenylphosphine azide, DIEA, DMF, RT, overnight (68%) or 9-fluorenylamine 3, isobutyl chlorocarbonate, N-methylmorpholine, DMAP, DCM, –20°C to RT, 5 h (65%); (iv) NaOH 5%, EtOH, RT, 6 h (98%); (v) H-Thr-OBn, EDCI, HOBt, DIEA, DMF, RT, overnight (17a: 80%; 17b: 78%); (vi) Dess-Martin periodinane, DCM, RT, 1 h; (vii) triethylamine, DMAP, DCM, RT, 1 h then Ph₃P, I₂, 0°C to RT, 2 h (18a: 81%; 18b: 87%); (viii) TFA, DCM, RT, 3 h (95%).

Fig. 6.

Synthesis of the linear trimer and macrocyclization step. Reagents and conditions: (i) EDCI, HOBt, DIEA, DMF (70%); (ii) H₂/Pd-C (10%); (iii) 8b, EDCI, HOBt, DIEA, DMF (60%, two steps); (iv) H₂/Pd-C (10%); (v) C₆F₅OH, N,N-dicyclohexylcarbodiimide, DCM; (vi) TFA, DCM, RT, 3 h (82%, three steps); (vii) DMAP, toluene, 95°C (72%).

Fig. 7.

Introduction of the lysine side chain. Reagents and conditions: (i) LiOH·H₂O, acetone, RT, 30 min (72%); (ii) εt-Boc-l-lysine, EDCI, HOBt, DMF, DIEA (85%); (iii) TFA, DCM, RT, 3 h (quantitative).