St. Louis Laboratories, Pfizer Global Research and Development, Pfizer, Inc., 700 Chesterfield Parkway West, Chesterfield, Missouri 63017, USA.
J Med Chem. 2010 Aug 26;53(16):5979-6002. doi: 10.1021/jm100505n.
We have discovered a novel class of nonsteroidal pyrazoline antagonists of the mineralocorticoid receptor (MR) that show excellent potency and selectivity against other nuclear receptors. Early analogues were poorly soluble and had a propensity to inhibit the hERG channel. Remarkably, both of these challenges were overcome by incorporation of a single carboxylate moiety. Structural modification of carboxylate-containing lead R-4g with a wide range of substituents at each position of the pyrazoline ring resulted in R-12o, which shows excellent activity against MR and reasonable pharmacokinetic profile. Introduction of conformational restriction led to a novel series characterized by exquisite potency and favorable steroid receptor selectivity and pharmacokinetic profile. Oral dosing of 3S,3aR-27d (PF-3882845) in the Dahl salt sensitive preclinical model of salt-induced hypertension and nephropathy showed blood pressure attenuation significantly greater than that with eplerenone, reduction in urinary albumin, and renal protection. As a result of these findings, 3S,3aR-27d was advanced to clinical studies.
我们发现了一类新型的非甾体吡唑啉类盐皮质激素受体（MR）拮抗剂，对其他核受体具有优异的效力和选择性。早期的类似物溶解度差，并且有抑制 hERG 通道的倾向。值得注意的是，通过引入单个羧基部分克服了这两个挑战。对含有羧基的先导化合物 R-4g 进行结构修饰，在吡唑啉环的每个位置引入各种取代基，得到了 R-12o，它对 MR 具有优异的活性和合理的药代动力学特征。引入构象限制导致了一个新的系列，其特点是具有极高的效力和良好的甾体受体选择性和药代动力学特征。在盐诱导的高血压和肾病的 Dahl 盐敏感临床前模型中，口服给予 3S,3aR-27d（PF-3882845），其降压作用明显大于依普利酮，同时降低尿白蛋白，并具有肾脏保护作用。由于这些发现，3S,3aR-27d 被推进到临床研究。
