Derivados de 4,5-DIHIDRO-1H-PIRAZOL como inhibidores selectivos de nNOS: síntesis y relaciones estructura-actividad

  1. Chayah, M 1
  2. Camacho, M.E 1
  3. Carrión, M.D 1
  4. Entrena, A 1
  5. Gallo, M.A 1
  6. Espinosa, A 1
  7. Acuña-Castroviejo, D 2
  1. 1 Universidad de Granada
    info
    Universidad de Granada

    Granada, España

    ROR https://ror.org/04njjy449

    Geographic location of the organization Universidad de Granada
  2. 2 Centro de Investigaciones Biomédicas (Armilla, Granada)
Journal:
Ars pharmaceutica

ISSN: 2340-9894,  0004-2927

Year of publication: 2010

Volume: 51

Issue: 3

Pages: 77-83

Type: Article

DIALNET GOOGLE SCHOLAR HANDLE: https://hdl.handle.net/10481/26337

More publications in: Ars pharmaceutica

Digibug. Repositorio Institucional de la Universidad de Granada: lock_openOpen access Handle

Sustainable development goals

Abstract

INTRODUCTION: Nitric Oxide Synthase (NOS) is the enzyme which catalyses the biosynthesis of Nitric Oxide (NO) from L-arginine1. Four NOS isoforms have been described:2 nNOS, iNOS, eNOS and mtNOS. NO is a biological messenger involved in several physiologic processes.3 However, an overproduction of NO by nNOS produces neurotoxicity which has been associated with various neurological disorders4. Therefore, it is necessary to found nNOS inhibitors to fight pathologies such as Alzheimer’s disease, Parkinson, amyotrophic lateral sclerosis and Huntington’s disease. In previous papers, our research group have described the synthesis of a series of kynurenine5 1 and kynurenamine6 2 derivatives as neuroprotective agents which are not active versus kynurenine-3- hydroxylase (KYN3OH). This fact demonstrates that their neuroprotective activity is only due to the nNOS inhibition. OBJECTIVE: Basing on these precedents, we have developed and evaluated in vivo, versus nNOS and iNOS, a series of 4,5-dihydro-1H-pyrazole derivatives with general structure 3 in order to find new selective compounds. METHODOLOGY: Taking kynurenine and kynurenamine derivatives as reference, we have synthesized rigid analogous with a ring of 4,5-dihydro-1H-pyrazole . Besides the conformacional restriction, other modifications have been carried out, as the introduction of different substituents in the aromatic ring and the modification of the acyl group in the pyrazoline ring. CONCLUSION /DISCUSION: All compounds inhibit nNOS. In most of cases, the inhibition of iNOS is negligible. Thus, they can be considered selective. On the other hand, there is no KYN3OH inhibition. Consequently, the neuroprotective potential of these derivatives is due only to the inhibition of nNOS.

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