Preclinical Development of Geranylgeranyl Disphosphate Synthase Inhibitors as Ant

描述（由申请人提供）：拟议研究的总体目标是确定将我们的新型GGDPS特异性抑制剂用于骨髓瘤和骨转移性疾病治疗的临床开发的可行性。这些新型的非含氮双膦酸盐，尤其是LWS-138，在领先的商业替代品中表现出的特异性使它们成为进一步开发临床应用的有利候选者。该项目的第一阶段包含四个具体目标，旨在证明这一前提的可行性。制定这些目标是为了允许对我们在初步工作中确定的三种潜在先导化合物中的每一种作出批准或不批准的决定。我们计划为这些研究制作足够的先导系列成员（4-5克）。我们将同时进行方法开发和验证，以在细胞培养基、细胞裂解液和小鼠血浆中定量测定每种候选物质。初步的可行性研究将包括代谢、膜通透性和血浆蛋白结合的体外药代动力学研究；以及对小鼠异种乳腺癌和前列腺癌模型的体内疗效研究。从这些研究中，我们将优先考虑这些化合物，作为第二阶段建议的一部分，在更复杂的转移性骨病模型中进行进一步研究。据估计，2005年将有大约50万例乳腺癌、前列腺癌或多发性骨髓瘤的新诊断，这一年死于这些癌症的总人数将达到82 000人。几乎所有介于这两点之间的患者都会在某个时候出现转移性骨病。局限于骨骼的转移性疾病比内脏转移性疾病的预期寿命更长，但也有显著的发病率；因此，能够降低这一大群患者发病率的新疗法显然会使公众受益。

DESCRIPTION (provided by applicant): The overall goal of the proposed studies is to establish the feasibility of moving our novel class of GGDPS specific inhibitors into clinical development for treatment of myeloma and metastatic disease of the bone. The specificity that a number of these novel non-nitrogen- containing bisphosphonates, most notably LWS-138, exhibit over the leading commercial alternatives makes them favorable candidates for further development aimed at clinical usage. Phase One of this project contains four specific aims designed to prove feasibility of this premise. These aims are formulated to allow a go/no-go decision on each of three potential lead compounds we have identified in our preliminary work. We plan to make enough of each member of our lead series for these studies (4-5 grams). We will concurrently carry out method development and validation for quantitative determination of each of these candidates in cell culture media, cell lysate, and mouse plasma. The primary feasibility studies will entail a combination of in vitro pharmacokinetic studies of metabolism, membrane permeability, and plasma protein binding; and in vivo efficacy studies in mouse xenograft breast and prostate cancer models. From these studies we will prioritize the compounds for further study in more elaborate models of metastatic bone disease as part of a Phase Two proposal. It was estimated that there would be approximately 500,000 new diagnoses of cancers of the breast, prostate or multiple myeloma in 2005, and that deaths from these cancers in that year would reach a total of 82,000. Nearly all of the patients who are somewhere between these two points in the disease progression will present with metastatic bone disease at some time. Metastatic disease confined to the skeleton is associated with a longer life expectancy than visceral metastasis but also with significant morbidity; therefore new therapies which could lessen the morbidity in this large group of patients would clearly benefit the public.