일반적인 신약 개발 방법으로는 천연물로부터 선도화합물이 발견되었을 때 의약화학자들은 그 물질의 화학구조식 중에서 약리 작용에 필수 요건이 되는 구조 요소를 규정하고, 체계적인 분자변형을 통하여 약리 작용의 최적화 작업을 추진한다. 그러나 분자 내에 여러 가지 치환기를 도입할 수 있는 경우 수많은 유도체가 합성 가능하며, 실제로 이와 같은 많은 수의 유도체를 합성한다는 것은 현실적으로 불가능하다. 통계적으로 하나의 신약 개발에 드는 시간과 경비는 약 10년 이상의 기간과 3,000 억원 이상의 경비가 소요된다. 따라서 시간과 경비를 줄이는 노력의 하나로 실험분야에서는 조합 화학합성 (Combinatorial Chemical Synthesis, CCS) 기술인 새로운 개념의 고효율 합성 기술이나 이를 대량 검색할 수 있는 초고속 활성 검색법 (High Through-put Screening, HTS) 기술이 1990년대 초에 본격적으로 각광 받게되었고, 정보관리 시스템을 통한 library 구축, 컴퓨터를 이용한 구조-활성 관계 및 분자 설계 기법이 급속히 발전하게 되었다. 따라서 기존의 random screening에 의한 신약개발 방법으로부터 탈피하여 새로운 차원의 신의약 개발 방법의 필요성이 절실히 요구되고 있다.

Of 16 million diabetic patients in the USA, 2.4 millions have experienced diabetic foot ulcer and 67,000 have amputations every year. For treatment of diabetic foot ulcer, Americans spend more than $1 billion each year, including $36,000 per patient for complete treatment and $60,000 for each amputation. Neuropathy and ischemia, two common complications of diabetes mellitus, are the primary underlying risk factors for development of diabetic foot ulcers. Ischemic ulcers develop as a result of low perfusion pressure in the foot with inadequate blood supply, whereas neuropathic ulcers develop from loss of protective sensation. In addition, diabetes also increases the risk of infection by impairing the body's ability to eliminate bacteria. From these circumstances, results are chronic wounds with impaired healing ability.

Recently, free radicals such as active oxygen species, nitric oxide, etc are believed to be one of the key substances in physiological and pathological, toxicological phenomena, and oxidative damages, and all organism have defencing system against such as free radicals. Formation and extinction of free radicals may be regulated through bio-redox system, in which various enzymes and compounds should be involved in very complicated manner. Thus, direct and non-invasive measurement of in vivo free radical reactions with living animals must be essential to understand the role of free radicals in pathophysiological phenomena. Electron spin resonance spectroscopy (ESR) is very selective and sensitive technique to detect free radicals, but a conventional ESR spectrometer has large detect in application to living animals, since high frequent microwave is absorbed with water, resulting in generation of high fever in living body. In order to estimate in vivo free radical reactions in living whole animals, we develop in vivo ESR-CT technique using nitroxide radicals as spin probes. Nitroxide radicals and their reduced forms, hydroxylamines, are known to interact with various redox systems. We found that! ! the signal decay due to reduction of nitroxyl radicals is influenced by aging, inspired oxygen concentration, ischemia-referfusion injury, radiation, etc. In the present paper, I will introduce in vivo ESR technique and my laboratory recent results concerning non-invasive evaluation of free radical reactions in living mice.

Despite the advances made in the past few decades in cancer chemotherapy, many conventional anticancer drugs display relatively poor selectivity for cancer cells. The nonselectivity of anticancer drugs and the development of anticancer drug resistance have been recognized as serious limitations in their clinical usefulness. Therefore, a major challenge in cancer chemotherapy is the development of new anticancer agents with improved selectivity for tumor cells as well as the prevention of the host cell resistance, both of which result in the improvement of therapeutic effect against cancer cells. Cyclophosphamide (CP), a widely used anticancer agent, is a prodrug that is activated by hepatic microsomal mixed-function oxidase (MFO) catalyzed C$_4$- hydroxylation. The resulting 4-hydroxycyclophosphamide (4-OH-CP) is converted to the ring-opened tautomer to aldophosphamide (Aldo) which subsequently undergoes a base- catalyzed ${\beta}$-elimination to generate cytotoxic phosphoramide mustard (PDA) and acrolein. The cytotoxic activity of CP is attributed to the aziridinium ion species derived from PDA that cross-links interstrand DNA.

The cycloooxygenase enzymes catalyze the oxidative conversion of arachidonic acid into prostag1andin H$_2$Which mediates both benificial and pathological effects. The COX-1 is constitutively expressed in most tissues and in blood platelets wherease the expression of COX-2 isoform is induced in response to inflmmatory stimuli such as cyctokynes. Thus the identification of a novel COX-2 selective inhibitor should offer excellent antiinflammatory activity with minimal side effects such as gastrointestinal toxicity. Recently, a group of structurally unique and biologically active pimarane diterpenoids has been isolated from indigenous Korean medicinal plants. These new diterpenoids turned out to be potential analgesic and antiinflammatory agent due to their potent inhibitory activities of prostaglandin synthesis. We have also found that the inhibition of PGE$_2$synthesis is attributed to the potent COX inhibition by pimarane diterpenoid in arachidonic acid cascade. In conjunction with development of new analgesic and nonsteroidal antiinflammatory agent, a series of works on these diterpenoids have been extensively carried out in our laboratories. These efforts involve the structure-activity relationship of pimaradienoic acid, molecular modelings and COX inibitory activities as well as actiinflammatory effects of its structural analogues. In addition, the total syntheses of the new natural pimarane diterpenoids, their stereoisomers and other structural variants were intensively investigated.

Transient forebrain ischemia results in delayed neuronal death in the CA1 region of the hippocampus after injury, which is, at least in part, a consequence of excessive generation of reactive oxygen species. Previous in vitro studies using cell cultures or brain slices have demonstrated that phospholipase D (PLD) in the nervous system is involved in the signaling mechanism in response to a variety of agonists. Several recent studies have shown that reactive oxygen species stimulate phospholipase D (PLD) activity in several kinds of cells. Therefore, this raises the possibility that PLD activity is enhanced in the ischemic brain. Meanwhile, osteopontin (OPN) was initially identified as a sialoglycoprotein in bone, but has since been found in various tissues. Although not much is known about its function, OPN seems to play an important role in inflammation and tissue repair. Recently, it was reported that OPN was upregulated in the activated microglia after focal brain ischemia, suggesting that OPN might play a role in wound healing after a focal stroke.

Heterotrimeric G Proteins transduce ligand binding to a wide variety of seven transmembrane cell surface receptors into intracellular signals. The currently accepted model for the activation of G protein suggests that ligand-activated receptor accelerates GDP-GTP exchange reactions on the ${\alpha}$ subunit of the heterotrimeric G protein. At least seventeen distinct isoforms of the G${\alpha}$ subunit protein have been identified in mammalian organisms. Among them, the G${\alpha}$q family consists of five members whose ${\alpha}$ subunits show different expression patterns. G${\alpha}$q and G${\alpha}$11 seem to be almost ubiquitously expressed, whereas G${\alpha}$14 is predominantly expressed in spleen, lung, kidney and testis. G${\alpha}$16 and its murine counterpart G${\alpha}$15 are expressed in hematopoietic cells and has been shown to couple a wide variety of receptors to phosphoinositide-specific phospholipase C activity. Beta-isoforms of phospholipase C were shown to be activated by all members of G${\alpha}$q family, i.e., G${\alpha}$q, G${\alpha}$11, G${\alpha}$l4 and G${\alpha}$16 subunits either in reconstitution system. or in experiments using cDNA transfection with intact Cos-7 cells.

아세트아미노펜(파라세타몰)은 p-aminophenol 유도체로서 (그림 1) 두통, 치통, 신경통 등의 통증에 널리 사용되는 해열진통제인데 아스피린과 같은 정도의 해열 진통 효과를 나타내며, 이것은 중추신경계의 체온조절 중추에 작용하여 피부혈관을 확장함으로써 열의 확산을 증가시키는 해열작용과 시상 및 대뇌피질에의 통각역치를 높여 진통작용을 하는 것으로 추정 된다. 아세트아미노펜은 백색의 결정 또는 결성성 가루로 물에 조금 녹고 메탄올 또는 에탄올에 잘 녹으며 수산화나트륨 시액에 녹고 에텔에는 매우 녹기 어렵다 (표1). 대한약전에서는 정제가, 미국약전에는 캅셀제, 좌제, 경구현탁액제, 발포성 건조시럽, 정제 등이 수재되어 있고, 세계 각국에서 OTC 제품으로 1정당 160mg의 츄잉정까지 판매되고 있다. 그러나, 시판되고 있는 정제등은 붕해되어 용출되는데 오랜시간이 소요되어 대한약전에는 약 30분간에 80%이상의 용출기준이 설정되어 있으며, 독특한 쓴맛 때문에 microencapsulation 한 제피세립을 사용하고 있으나 역시 1 정당 300mg 이상의 확산정이나 속용정은 존재하지 않는다. 이것을 개선하기 위하여 붕해속도가 빠르고 특히 진통효과가 빠르며 물없이 구강내에서 간편히 녹여 복용하거나 또는 씹어서 또는 물과 함께 복용할 수 도 있는 $\ulcorner$알카펜$\lrcorner$ 속용정을 개발하게 되었다 (그림2).