Privileged substructures are of potentially great importance in medicinal chemistry. These scaffolds are characterized by their ability to promiscuously bind to a multitude of receptors through a variety of favorable characteristics. This may include presentation of their substituents in a spatially defined manner and perhaps also the ability to directly bind to the receptor itself, as well as exhibiting promising characteristics to aid bioavailability of the overall molecule. It is believed that some privileged substructures achieve this through the mimicry of common protein surface elements that are responsible for binding, such as β- and gamma;-turns. As a result, these structures represent a promising means by which new lead compounds may be identified.

The combinatorial synthesis of bicyclic privileged structures or privileged substructures

The parametrization and validation of the OPLS3 force field for small molecules and proteins are reported. Enhancements with respect to the previous version (OPLS2.1) include the addition of off-atom charge sites to represent halogen bonding and aryl nitrogen lone pairs as well as a complete refit of peptide dihedral parameters to better model the native structure of proteins. To adequately cover medicinal chemical space, OPLS3 employs over an order of magnitude more reference data and associated parameter types relative to other commonly used small molecule force fields (e.g., MMFF and OPLS_2005). As a consequence, OPLS3 achieves a high level of accuracy across performance benchmarks that assess small molecule conformational propensities and solvation. The newly fitted peptide dihedrals lead to significant improvements in the representation of secondary structure elements in simulated peptides and native structure stability over a number of proteins. Together, the improvements made to both the small mole...

OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins

The concept of isosterism between relatively simple chemical entities was originally contemplated by James Moir in 1909, a notion further refined by H. G. Grimm’s hydride displacement law and captured more effectively in the ideas advanced by Irving Langmuir based on experimental observations. Langmuir coined the term “isostere” and, 18 years in advance of its actual isolation and characterization, predicted that the physical properties of the then unknown ketene would resemble those of diazomethane. The emergence of bioisosteres as structurally distinct compounds recognized similarly by biological systems has its origins in a series of studies published byHans Erlenmeyer in the 1930s, who extended earlier work conducted by Karl Landsteiner. Erlenmeyer showed that antibodies were unable to discriminate between phenyl and thienyl rings or O, NH, and CH2 in the context of artificial antigens derived by reacting diazonium ions with proteins, a process that derivatized the ortho position of tyrosine, as summarized in Figure 1 The term “bioisostere” was introduced by Harris Friedman in 1950 who defined it as compounds eliciting a similar biological effect while recognizing that compounds may be isosteric but not necessarily bioisosteric. This notion anticipates that the application of bioisosterism will depend on context, relying much less on physicochemical properties as the underlying principle for biochemical mimicry. Bioisosteres are typically less than exact structural mimetics and are often more alike in biological rather than physical properties. Thus, an effective bioisostere for one biochemical application may not translate to another setting, necessitating the careful selection and tailoring of an isostere for a specific circumstance. Consequently, the design of bioisosteres frequently introduces structural changes that can be beneficial or deleterious depending on the context, with size, shape, electronic distribution, polarizability, dipole, polarity, lipophilicity, and pKa potentially playing key contributing roles in molecular recognition and mimicry. In the contemporary practice of medicinal chemistry, the development and application of bioisosteres have been adopted as a fundamental tactical approach useful to address a number of aspects associated with the design and development of drug candidates. The established utility of bioisosteres is broad in nature, extending to improving potency, enhancing selectivity, altering physical properties, reducing or redirecting metabolism, eliminating or modifying toxicophores, and acquiring novel intellectual property. In this Perspective, some contemporary themes exploring the role of isosteres in drug design are sampled, with an emphasis placed on tactical applications designed to solve the kinds of problems that impinge on compound optimization and the long-term success of drug candidates. Interesting concepts that may have been poorly effective in the context examined are captured, since the ideas may have merit in alternative circumstances. A comprehensive cataloging of bioisosteres is beyond the scope of what will be provided, although a synopsis of relevant isosteres of a particular functionality is summarized in a succinct fashion in several sections. Isosterism has also found productive application in the design and optimization of organocatalysts, and there are several examples in which functional mimicry established initially in a medicinal chemistry setting has been adopted by this community.

Synopsis of some recent tactical application of bioisosteres in drug design.

Compounds Currently in Phase II−III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas Yu Zhou,† Jiang Wang,† Zhanni Gu,† Shuni Wang,† Wei Zhu,† Jose ́ Luis Aceña,*,‡,§ Vadim A. Soloshonok,*,‡,∥ Kunisuke Izawa,* and Hong Liu*,† †Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China ‡Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizab́al 3, 20018 San Sebastiań, Spain Department of Organic Chemistry, Autońoma University of Madrid, Cantoblanco, 28049 Madrid, Spain IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3, 48013 Bilbao, Spain Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka, Japan 533-0024

Next Generation of Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase II–III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas

The cardiovascular and other actions of angiotensin II (Ang II) are mediated by AT(1) and AT(2) receptors, which are seven transmembrane glycoproteins with 30% sequence similarity. Most species express a single autosomal AT(1) gene, but two related AT(1A) and AT(1B) receptor genes are expressed in rodents. AT(1) receptors are predominantly coupled to G(q/11), and signal through phospholipases A, C, D, inositol phosphates, calcium channels, and a variety of serine/threonine and tyrosine kinases. Many AT(1)-induced growth responses are mediated by transactivation of growth factor receptors. The receptor binding sites for agonist and nonpeptide antagonist ligands have been defined. The latter compounds are as effective as angiotensin converting enzyme inhibitors in cardiovascular diseases but are better tolerated. The AT(2) receptor is expressed at high density during fetal development. It is much less abundant in adult tissues and is up-regulated in pathological conditions. Its signaling pathways include serine and tyrosine phosphatases, phospholipase A(2), nitric oxide, and cyclic guanosine monophosphate. The AT(2) receptor counteracts several of the growth responses initiated by the AT(1) and growth factor receptors. The AT(4) receptor specifically binds Ang IV (Ang 3-8), and is located in brain and kidney. Its signaling mechanisms are unknown, but it influences local blood flow and is associated with cognitive processes and sensory and motor functions. Although AT(1) receptors mediate most of the known actions of Ang II, the AT(2) receptor contributes to the regulation of blood pressure and renal function. The development of specific nonpeptide receptor antagonists has led to major advances in the physiology, pharmacology, and therapy of the renin-angiotensin system.

https://pharmrev.aspetjournals.org/content/pharmrev/52/3/415.full.pdf

International Union of Pharmacology. XXIII. The Angiotensin II Receptors

Nonpeptide Angiotensin II Receptor Antagonists: The Next Generation in Antihypertensive Therapy

TITLE OF THE INVENTION: IMPROVED PROCESS FOR PREPARING ACHPA ABSTRACT OF THE DISCLOSURE A process for preparing (3S,4S)-N-.alpha.-BOC)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid ethyl ester comprising (a) reacting the N-.alpha.-BOC-amino-3-hexahydrophenyl propionic acid with 1,1-carbonyldiimidazole, to form an acylimidazol-activated derivative of said acid; (b) coupling said acylimidazole-activated derivative with the magnesium salt of malonic acid monoethylester to afford the .beta.-ketoester; (c) reducing said .beta.-ketoester using sodium cyanoborohydride in tetrahydrofuran and glacial acetic acid to produce a mixture of (3S,4S)-(N.alpha.-BOC)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid ethyl ester and (3B,4S)-(N.alpha.-BOC)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid ethyl ester; (d) crystallizing off the (3R,4S) compound and purifying the remaining product to afford optically-pure (3S,4S)-(N.alpha.-BOC)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid.

Process for preparing ACHPA

Process for producing imidazo-condesed 6-membered heterocyclic compounds and blood-pressure reducing pharmaceutical preparatives containing these compounds as active substance

Discovery of hydroxy pyrimidine Factor IXa inhibitors.

NEW MATERIAL: A compound of formulae I and II [R 1 is COR 2 R 7 , SO 2 R 3 , formula III, etc.; R 2 and R 3 are each H, halo, NO 2 , NH 2 , alkyl, etc.; R 4 is H or alkyl; R 5 is H, halo, alkyl, phenyl, naphthyl, etc.; R 6 is alkyl, alkenyl, phenyl, etc.; A is formulae IV-VI; B is C(OH)H, CO, O, etc.; (p) is 0 or 1; X is CO, O, S(O) y (y is 0-2), etc.; (r) is 1 or 2; (q) is 0 or 1; R 7 is H, alkyl, etc.; R 8 is H or formula VII (R 4a is alkyl); R 9 is R 7 ; R 11 is H, alkyl, etc.; Q is NHCOR 26 , NHSO 2 -alkyl, etc.; T is CO 2 R 23 , CN, etc.; R 23 is H or alkyl; R 26 is aryl, etc.]. EXAMPLE: 4-Amino-2-butyl-5-carbomethoxy-1-[(2'-carboxybiphen-4-yl)methyl]- imidazole. USE: Angiotensine II antagonists. PROCESS: A compound of formula I is obtained, for example, by reacting a compound of formula VIII with a compound of formula IX to give a compound of formula X and treating the compound with a bidentate ligand. COPYRIGHT: (C)1991,JPO

Angiotensine ii antagonist

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