Giordani A, Pevarello P, Cini M, Bormetti R, Greco F, Toma S, Speciale C, Varasi M
Pharmacia & Upjohn, Chemistry Dept., Nerviano, Milan, Italy.
Bioorg Med Chem Lett. 1998 Oct 20;8(20):2907-12. doi: 10.1016/s0960-894x(98)00517-4.
Kynurenine 3-hydroxylase (KYN 3-OHase) is a key enzyme in the kynurenine pathway of tryptophan degradation and its inhibition may be an effective mechanism for counteracting neuronal excitotoxic damage. We present here a new class of inhibitors derived from a structure-activity relationship (SAR) study of the benzoylalanine side-chain of 1. 2-hydroxy-4-(3,4-dichlorophenyl)-4-oxobutanoic acid (8) and 2-benzyl-4-(3,4-dichlorophenyl)-4-oxo-butanoic acid (10) emerged as the most interesting derivatives. Enantiospecific synthesis for both enantiomers of 8 and diastereomeric salt resolution for those of 10 were successfully applied.
犬尿氨酸3-羟化酶（KYN 3-OHase）是色氨酸降解犬尿氨酸途径中的一种关键酶，抑制该酶可能是对抗神经元兴奋性毒性损伤的有效机制。我们在此展示了一类新的抑制剂，这些抑制剂源自对1的苯甲酰丙氨酸侧链的构效关系（SAR）研究。2-羟基-4-（3,4-二氯苯基）-4-氧代丁酸（8）和2-苄基-4-（3,4-二氯苯基）-4-氧代丁酸（10）成为最具吸引力的衍生物。成功应用了对8的两种对映体的对映体特异性合成以及对10的非对映体盐拆分。
