Lipophilic antifolates and AIDS opportunistic infections

描述（由申请人提供）：本延续的总体目标 项目是发现针对卡氏肺孢子虫（Pc）的新药， 弓形虫（Tg）、鸟分枝杆菌（My）和微小隐孢子虫 (Cp)，四种已知会导致发病率和死亡率的机会性病原体， 艾滋病患者。更具体地说，该项目将侧重于设计和 几类单环和双环二氨基嘧啶的合成 我们希望这些衍生物能联合收割机结合三甲曲沙（TMQ）的高效性， 和吡嗪肟（PTX），具有甲氧苄啶（TMP）的物种选择性， 乙胺嘧啶（PM）对Pc、Tg或Cp二氢叶酸还原酶（DHFR）的作用， 啮齿动物或人DHFR。TMQ和PTX的结合选择性的缺乏需要 它们与亚叶酸（LV）一起使用，以防止血液毒性，而 TMP和PM作为单一药剂的相对低的功效要求它们被 与磺胺类药物和其他药物一起使用，经常引起无法忍受的副作用 方面的影响.因此，新的DHFR抑制剂，既有效，选择性将是 非常可取。待研究的化合物包括几种二氨基嘧啶 环系统与短的CH 2桥的芳基侧链。的理由 短桥是，如果活性位点在空间上不太适应， Pc或其他非哺乳动物DFHR，而不是哺乳动物DHFR，最佳疏水性 当进入活性部位的抑制剂部分被 相对紧凑（即，更像TMP而不是TMQ）。我们还将测试 假设实现选择性有效方法是 2，4-二氨基-5-[（2-甲氧基-和3，4-二甲氧基-5-（C3 - 9）烷氧基）-苄基] 在末端含有酸性羧基或四唑基团的嘧啶 O-烷基侧链。这个类的一个非常有前途的例子是 2，4-二氨基-5-[2-甲氧基-5-（4-羧基丁基）苄基]嘧啶（PY657），其为 我们最近发现，它具有出色的效力和选择性， PC和Ma DHFR。还提出了另一个的第二代类似物 我们在这个项目中发现的铅化合物， N-（2，4-二氨基蝶啶-6-基）甲基二苯并[B，f]氮杂卓（PT 653）。PT653是 对Tg和Ma DHFR选择性有效，但其生物利用度有限 低水溶性。上具有COOH、NH2或OH基团的PT 653的类似物 三环部分及其前药的制备目的是 改善水溶性而不牺牲效力或选择性。

DESCRIPTION (Provided by the applicant): The overall goal of this continuation project is the discovery of new drugs against Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), Mycobacterium avium (My), and Cryptosporidium parvum (Cp), four opportunistic pathogens known to cause morbidity and mortality in AIDS patients. More specifically, the project will focus on the design and synthesis of several classes of mono- and dicyclic diamino-pyrimidine derivatives that we hope will combine the high potency of trimetrexate (TMQ) and piritrexim (PTX) with the species selectivity of trimethoprim (TMP) and pyrimethamine (PM) against Pc, Tg, or Cp dihydrofolate reductase (DHFR) versus rodent or human DHFR. The lack of binding selectivity of TMQ and PTX requires that they be used with leucovorin (LV) to prevent hematologic toxicity, whereas the relatively low efficacy of TMP and PM as single agents requires them to be used with sulfonamides and other drugs that often cause intolerable side effects. Thus, new DHFR inhibitors that are both potent and selective would be highly desirable. Compounds to be studied include several diaminopyrimidine ring systems with a short CH2 bridge to the aryl side chain. The rationale for a short bridge is that, if the active site is sterically less accommodating in Pc or other non-mammalian DFHR than in mammalian DHFR, optimal hydrophobic contact should occur when the part of the inhibitor entering the active site is relatively compact (i.e., more like TMP than TMQ). We will also test the hypothesis that an effective way to achieve selectivity is with 2,4-diamino-5-[(2-methoxy- and 3,4-dimethoxy-5-(C3-9)alkoxy)-benzyl] pyrimidines containing an acidic carboxyl or tetrazole group at the end of the O-alkyl side chain. A very promising example of this class is 2,4-diamino-5-[2-methoxy-5-(4-carboxybutyl)benzyl]pyrimidine (PY657), which was recently discovered by us to have excellent potency and selectivity against both Pc and Ma DHFR. Also proposed are second-generation analogs of another lead compound we discovered in this project, N-(2,4-diaminopteridin-6-yl)methyldibenz[b,f]azepine (PT653). PT653 is selectively potent against Tg and Ma DHFR, but its bioavailability is limited by low aqueous solubility. Analogs of PT653 with a COOH, NH2, or OH group on the tricyclic moiety, and prodrugs thereof, will be made with the goal of improving aqueous solubility without sacrificing potency or selectivity.