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  • thirdmeinvestor thirdmeinvestor Sep 27, 2012 7:26 PM Flag

    New Phase 2 to expand Kalydeco label.

    The work shown in Abstract #30 was definitely done at Vertex. But the compound VRT-534 was obtained through the CFF. They found that this particular form is more potent than its chemical isomers(mirror images of VRT-534). The authors think that the compound is a useful tool rather than a drug candidate itself. But it is clear that Van Goor et al. are up to something in the line of correctors beyond VX-809 and 661. See below.

    AUTHORS (LAST NAME, FIRST NAME): Grootenhuis, Peter 1; Hadida, Sabine 1; Miller, Mark

    1; Zhou, Jinglan 1; Van Goor, Fredrick 1
    INSTITUTIONS (ALL): 1. Vertex Pharmaceuticals Incorporated, San Diego, CA, United States.

    ABSTRACT BODY: VRT-534 (C-18) is a cystic fibrosis transmembrane conductance regulator (CFTR) corrector made available through the CF Foundation for research purposes. We describe some in vitro characteristics of C-18 and the effect of its chiral centers on activity. Extensive medicinal chemistry and SAR analyses on VRT-768, an initial corrector hit, led to several distinct chemical scaffolds, one of which led to VRT-534. The two chiral centers of C-18 allow for four discrete stereoisomers. We studied the corrector activity of the various stereoisomers by monitoring chloride transport in Ussing chamber studies using cultured primary human bronchial epithelial cells derived from patients with cystic fibrosis who are homozygous for the F508del-CFTR mutation. The chiral center in the benzylic position was found to display a profound effect on the potency. Thus, C-18 (S,R-configuration) was more potent (EC50=0.5 μM) than VRT-535 (R,R-configuration) which had an EC50=2.7 μM. Interestingly, the maximal efficacy of these diastereoisomers was similar. Changing the R-configuration of the hydroxypyrrolidine to S led to 3-fold decrease in potency. To our knowledge, this is the first instance of a clear stereochemical preference for a CFTR corrector; this supports a specific interaction with the putative target. The in vitro potency and efficacy of C-18 render it a useful tool for research into CFTR correction.
    Sponsored by Vertex Pharmaceuticals Incorporated.

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