A series of 3-aryl(pyrrolidin-1-yl)butanoic acids were synthesized using a diastereoselective route, via a rhodium catalyzed asymmetric 1,4-addition of arylboronic acids in the presence of (R)-BINAP to a crotonate ester to provide the (S) absolute configuration for the major product. A variety of aryl substituents including morpholine, pyrazole, triazole, imidazole, and cyclic ether were screened in cell adhesion assays for affinity against α_vβ₁, α_vβ₃, α_vβ₅, α_vβ₆, and α_vβ₈ integrins. Numerous analogs with high affinity and selectivity for the α_vβ₆ integrin were identified. The analog (S)-3-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid hydrochloride salt was found to have very high affinity for α_vβ₆ integrin in a radioligand binding assay (pK_i = 11), a long dissociation half-life (7 h), very high solubility in saline at pH 7 (>71 mg/mL), and pharmacokinetic properties commensurate with inhaled dosing by nebulization. It was selected for further clinical investigation as a potential therapeutic agent for the treatment of idiopathic pulmonary fibrosis.

中文翻译：

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发现（S）-3-（3-（3,5-二甲基-1 H-吡唑-1-基）苯基）-4-（（R）-3-（2-（5,6,7,8 -四氢-1,8-萘啶-2-基）乙基）吡咯烷-1-基）丁酸，非肽α _v β ₆整联抑制剂用于特发性肺纤维化的治疗吸入

在（R）-BINAP存在下，通过铑催化的芳基硼酸的不对称1,4-加成反应，使用非对映选择性路线合成了一系列3-芳基（吡咯烷-1-基）丁酸主要产品的（S）绝对配置。包括吗啉，吡唑，三唑，咪唑，和环醚的各种芳基取代基中的细胞粘附试验中筛选针对α亲和力_v β ₁，α _v β ₃，α _v β ₅，α _v β ₆，α _v β ₈整联蛋白。具有高亲和力和选择性的α众多类似物_v β ₆整联进行鉴定。类似物（S）-3-（3-（3,5-二甲基-1 H-吡唑-1-基）苯基）-4-（（R）-3-（2-（5,6,7,8 -四氢-1,8-萘啶-2-基）乙基）吡咯烷-1-基）丁酸盐酸盐被发现具有为α非常高的亲和力_v β ₆整联在放射性配体结合测定（对ķ_我= 11），较长的解离半衰期（7 h），在pH 7的盐水中具有很高的溶解度（> 71 mg / mL）和药代动力学特性，与通过雾化吸入给药相当。它被选作进一步的临床研究，作为治疗特发性肺纤维化的潜在治疗剂。