RESUMO
A series of trisubstituted cyclohexanes was designed, synthesized and evaluated as CC chemokine receptor 2 (CCR2) antagonists. This led to the identification of two distinct substitution patterns about the cyclohexane ring as potent and selective CCR2 antagonists. Compound 36 exhibited excellent binding (CCR2 IC(50)=2.4 nM) and functional antagonism (calcium flux IC(50)=2.0 nM and chemotaxis IC(50)=5.1 nM).
Assuntos
Química Farmacêutica/métodos , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/química , Sítios de Ligação , Cálcio/química , Quimiocina CCL2/química , Quimiotaxia , Cicloexanos/química , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Estrutura Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Carbocyclic uracil polyoxin C (+)-2 and its alpha-epimer (-)-3 were synthesized in an efficient fashion from cis-4-(N-tert-butylcarbamoyl)cyclopent-2-en-1-ol (+/-)-7. The synthesis incorporates a concise, inexpensive chemoenzymatic synthesis of enantiopure aminocyclopentenols, a Pd(0)-catalyzed substitution reaction, and a mild reduction of an alpha-nitro ester by TiCl(3)/sodium borohydride. Significantly, this process demonstrates the synthetic utility of the versatile enantiopure aminocyclopentenol building block (-)-4.
