Jasjit S. Bindra

Discovery of Inhibitors of Human Renin with High Oral Bioavailability

Knowledge of the sequence of a bioactive protein (angiotensinogen) and the availability of a natural product inhibitor lead (pepstatin) were the starting point for discovery of potent penta- and hexapeptide renin inhibitors. Study of the metabolism and disposition of these substances forced the discovery of simpler inhibitors leading to the discovery of oral activity in Terlakiren (22). Modification of physical properties led to the synthesis of aminopiperidine 30, which was identified by oral efficacy profiling. Structural modification to give enzymatic stability produced the bioavailable benzylsuccinate inhibitor 34. Its bioactive monomethylamine metabolite (35, CP-108,671) was subsequently found to have uniformly high oral bioavailability and activity in various species including primates.

Chapter 22. Anti-aging Drugs

Publisher Summary This chapter elaborates the development of antiaging drugs. Aging processes are increasingly being thought of as originating at the cellular or subcellular level, even though there is no general agreement as to the nature of these processes. The most attractive general hypothesis of aging is that senescence is primarily a cellular information loss phenomenon originating at the molecular level, and that dyshomeostasis of other kinds through loss of neuronal, endocrine, and immunological information is of a secondary nature. Changes in neurons and in cells in the microvascular system are the main cause of aging in mammals. The marked increase in life-span of rats on restricted caloric intake has been explained on the basis of continued high level of stress hormone secretion due to strengthened chalone action. The diversity of regulatory functions performed by the hypothalamus has led to the suggestion that age-dependent changes in the hypothalamus are responsible for the functional and metabolic changes associated with aging. Aging may affect protein synthesis, either at the DNA level by mutation, single strand breaks or other structural changes, or at subsequent stages. Decreased immunological surveillance may originate in the thymus-dependent segment of the immune system, and the latter, in turn, may be dependent on exhaustion of the Hayflick limit in thymus cells and dependent tissues.

Chapter 2 Oxindole Alkaloids

Publisher Summary The application of modern techniques of structural analysis, particularly proton magnetic resonance (PMR), 13 C magnetic resonance (CMR), mass spectrum, and circular dichroism (CD), has had considerable impact upon elucidation of the structure of oxindole alkaloids and has laid bare the finer details of their stereochemistry and conformation. In this chapter, important physical properties of most of the known oxindole alkaloids are included in tabular form for the purpose of comparison and providing a comprehensive overview of the members of this group. Recently, the mass spectrum of gelsemine was investigated and the molecule was found to undergo fragmentation by two principle pathways upon electron impact. The most intense ion in the gelsemine spectrum occurring at m/e 108 (M-214) is characteristic of the fragmentation pathway, while a second mode of fragmentation results in the ion at m/e 279, probably by extrusion of N b as CH 2 =N–CH 3 . The N b -methylene (C-21) protons must be adjacent to a tertiary carbon, because they appear as a pair of doublets at 2.32 and 2.786 and exhibit no additional coupling. The mass spectrum of gelsedine exhibits a molecular ion peak at m/e 238 and a peak at m/e 209 corresponding to the loss of an ethyl group. The correctness of the formula C 21 H 24 O 3 N 3 for gelsevirine has been demonstrated by a molecular ion peak at m/e 352 in the high-resolution mass spectrum of the base. The chapter also discusses oxindoles of secoyohimbane and heteroyohimbane type. A comparison of the PMR chemical shifts of majdine with pteropodine and carapanaubine suggests that all three bases have the same allo stereochemistry. Gambirdine and isogambirdine, the latter isolated as its hydrochloride, are a pair of interconvertible oxindoles of C 21 H 24 N 2 O 4 constitution. IR, UV, PMR, and mass spectral data suggest that both are alkaloids of the mitraphylloid type.

Back to Nature: The Alternative Paradigm for Drug Development

Nature has traditionally been a fruitful harbinger of new medicines. However, despite the history of past successes, interest in natural products as a source of new drugs has withered over the past two decades. The trend in drug research has been towards combinatorial chemistry and high throughput screens, relying on receptor mechanisms to identify leads for further development. Following passage of Dietary Supplement Health and Education Act (DSHEA) legislation in 1994 and the resurgence of interest in herbals and the dietary supplements market, natural products are again attracting attention as a potential source of new medicines. These developments are triggering powerful changes on how botanical mixtures are developed and regulated.

Chapter 27. Drug Receptors

Publisher Summary This chapter discusses studies that focus on drug receptors. Adrenergic agonists act by catalyzing adenyl cyclase and any general theory seeking to explain their action at a molecular level must be compatible with visualization of the receptor as an integral part of this enzyme system. Some recent data suggests that cyclic GMP may be involved in cholinergic neurotransmission. Studies have revealed that neurotransmitters exert their effect on postsynaptic cells by interacting with specific sites or receptors on the excitable membrane. This interaction initiates and controls the permeability changes permitting ion movements and amplification of the electrical signal during propagation of nerve impulses. An important characteristic of drug–receptor interaction is that not all agonists are equally effective in causing this permeability change. Different drugs are capable of producing an equal biological response when occupying different fractions of the receptor pool, an observation that led to the concept of “intrinsic activity” or efficacy, itself purely an operational term. The methodology and technique of affinity labeling of protein active sites was reviewed in another study. The method is found to be potentially useful in the study of molecular properties of drug receptors.