Synthesis and estrogenic properties of 17-epi-ethynylestradiol and its ether derivatives epimestranol and epiquinestrol.

The synthesis of 17-epi-ethynylestradiol (10), the 17 beta-ethynyl-17 alpha-ol epimer of the well-known orally active estrogen, ethynylestradiol (1), was achieved by LiA1H4 reduction of epoxide 9, as well as by demethylating epimestranol (11) with CH3MgI. Compound 11 was obtained by the unusual 17 beta-ethynylation of estrone 3-methyl ether 22 under equilibrating conditions. The in vitro estrogen receptor-binding affinity and the oral estrogenicity in the rat for the 17-epi compounds 10, 11 and 20 (epiquinestrol) was evaluated. Despite moderate estrogen receptor-binding affinity, compound 10 was devoid of measurable estrogenicity at 10 mg/kg or antiestrogenicity at 3 mg/kg.

17alpha-Ethyl-20alpha-and -20beta-dihydroprogesterones and other 17alpha-ethyl-substituted pregnanes as potential contragestational agents.

The 17alpha-ethyl-substituted analogs of the two epimeric 20-dihydroprogesterones, allopregnadedione and pregn-5-ene-3,20-dione, were synthesized and evaluated for their possible oral contragestational (postcoital antifertility) activity in the rat. The compounds, though bound strongly to the progesterone receptor in vitro, were inactive preimplantively at 10 mg/kg and postimplantively at 40 mg/kg in vivo.

PIP: 17alpha-20alpha- and 20beta-dihydroprogesterones and other 17alpha-ethyl-substituted pregnanes as potential contragestational agents were investigated in the rat, and the syntheses of 17 alpha-ethyl-substituted analogs of the 2 epimeric 20-dihydroprogesterones, allopregnanedione and pregn-5-ene-3,20 dione are presented. The compounds were administered orally to 5 rats on Days 1-6 of gestation for studies related to effects on implantation or on Days 9-12 of gestation for studies related to drug effects on pregnancy after implantation. Postmortem examination was carried out between Day 14 and Day 21 of gestation. The compounds were strongly bound to the pr ogesterone receptor in vitro but were inactive preimplantively at 10 mg/kg and postimplantively at 40 mg/kg in vivo.

Cardiotonic agents. Synthesis and inotropic activity of a series of isoquinolin-3-ol derivatives.

A series of isoquinolin-3-ol derivatives (II) was prepared as analogues of the clinical cardiotonic agent bemarinone (ORF 16600, I). Although in many respects the structural requirements for the cardiotonic activity of II are similar to those of bemarinone, certain differences between the series were noted. Our structure-activity studies show that II is less sensitive to alkoxy-substitution effects than is I, and more significantly, 4-substitution of II by alkyl groups, halogen, or alkanecarboxylic acid derivatives enhances cardiotonic activity in II in contrast to I, wherein analogous substitution eliminated activity. A linear correlation between contractile force (CF) increase and cyclic nucleotide phosphodiesterase fraction III (PDE-III) inhibition by the title compounds was determined. The isoquinoline derivatives were characteristically short-acting cardiotonic agents with good potency and selectivity.

Synthesis and antifertility activity of zoapatanol analogues.

The synthesis of and guinea pig contragestational screening data for several oxepane and 3,8-dioxabicyclo[3.2.1]octane analogues of zoapatanol (1) are described and their structure-activity relationships discussed. Conversion of the 5-keto group on the nonenyl side chain of 1 into a hydroxyl function enhanced the potency. Further significant enhancement in the potency was realized with the transformation of several oxepanes into the 3,8-dioxabicyclo-[3.2.1]octane-1-acetic acid derivatives. Detailed, comparative contragestational evaluation of the three most potent compounds 9, 33, and 37 is presented, which led to the selection of 33 (ORF 13811) for further biological evaluation.

Renal vasodilators. The role of the 4-substituent in isoquinolin-3-ol cardiovascular agents: 4-ureido derivatives of isoquinolin-3-ol with selective renal vasodilator properties.

The synthesis and cardiovascular evaluation of a series of isoquinolin-3-ol derivatives bearing a variety of nitrogen substituents (amino, acylamino, carbamate, and ureido) at C-4 are described. Certain of these compounds have a selective renal vasodilating profile and have minimal effects on arterial blood pressure or heart rate when administered intravenously in the instrumented anesthetized dog. The most potent renal vasodilator in the series is 4-(allylureido)-6,7-dimethoxyisoquinolin-3-ol (38), which at a dose of 1.2 mg/kg iv produces a 97% maximal increase in renal blood flow without significant hypotensive or chronotropic effects. Structure-activity observations on the nature of the 4-substituent and the alkoxy substitution pattern in the aromatic ring of the isoquinolinol nucleus are discussed.

Synthesis and cardiotonic activity of a series of substituted 4-alkyl-2(1H)-quinazolinones.

The synthesis, cardiac fraction III cyclic nucleotide phosphodiesterase (PDE-III) inhibition, and positive inotropic activity of a series of 2(1H)-quinazolinones are reported. A general synthesis of the series involved the cyclization of 2-aminoacetophenones with potassium cyanate in acetic acid. Modifications at the 4-position of the quinazoline nucleus were best achieved by formation of the intermediate N1-acyl-N3-phenylurea from the substituted phenyl isocyanate and appropriate carboxamide. PPA was used to ring close to the quinazoline product. Generally the SAR for the series paralleled the five-point model previously published for PDE-III inhibition. The most active analogue of the series was 5,6-dimethoxy-4-methyl-2(1H)-quinazolinone (1) (ORF 16600), which had about twice the intravenous potency of amrinone. Compound 1 is currently under development as an orally active cardiotonic.

Synthesis and SAR of 6-substituted purine derivatives as novel selective positive inotropes.

A series of purine derivatives was prepared and examined for selective inotropic activity in vitro and in vivo. Thioether-linked derivatives were superior to their oxygen and nitrogen isosteres. Substitution of electron-withdrawing groups on the benzhydryl moiety of these agents increased potency. The best compound of the study, 17 (carsatrin), was examined further and demonstrated selective oral activity as a positive inotrope. These compounds are presumed to act by affecting the kinetics of the cardiac sodium channel by analogy to the prototypic agent DPI 201106 (1). Their high selectivity for increasing contractile force and dP/dt without affecting blood pressure or heart rate is consistent with this mechanism. Carsatrin (17) was selected as a potential development candidate.

Substituted salicylanilides as inhibitors of two-component regulatory systems in bacteria.

A new class of inhibitors of the two-component regulatory systems (TCS) of bacteria was discovered based on the salicylanilide screening hits, closantel (1) and tetrachlorosalicylanilide (9). A systematic SAR study versus a model TCS, KinA/Spo0F, demonstrated the importance of electron-attracting substituents in the salicyloyl ring and hydrophobic groups in the anilide moiety for optimal activity. In addition, derivatives 8 and 16, containing the 2, 3-dihydroxybenzanilide structural motif, were potent inhibitors of the autophosphorylation of the KinA kinase, with IC50s of 2.8 and 6. 3 µM, respectively. Compound 8 also inhibited the TCS mediating vancomycin resistance (VanS/VanR) in a genetically engineered Enterococcus faecalis cell line at concentrations subinhibitory for growth. Closantel (1), tetrachlorosalicylanilide (9), and several related derivatives (2, 7, 10, 11, 20) had antibacterial activity against the drug-resistant organisms, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF).

Synthesis and biological evaluation of 2 - and 4- hydroxymestranol.

The synthesis of 2-hydroxy and 4-hydroxymestranol by oxidation of mestranol with m-chloroperbenzoic acid is described. The oral estrogenicity and contragestational activity of these and related catechol estrogen derivatives in the rat is also presented.

Synthesis and class III type antiarrhythmic activity of 4-aroyl (and aryl)-l-aralkylpiperazines.

The synthesis and in vitro Class III antiarrhythmic activity of several 4-aroyl (and aryl)-1-aralkylpiperazine and piperidine derivatives are described. Among several potent compounds identified in the series, RWJ-28810 (3), with its EC20 of 3 nM, ranks as one of the most potent (in vitro) compounds reported.

6-oxa isosteres of anacardic acids as potent inhibitors of bacterial histidine protein kinase (HPK)-mediated two-component regulatory systems.

A series of 6-oxa isosteres of anacardic acids (6-higher alkyl/alkenyl-2-hydroxybenzoic acids) was synthesised and several members were discovered to be among the most potent inhibitors (IC50 values < or = 5 microM) of the bacterial two-component regulatory systems, KinA/SpoOF and NRII/NRI, reported to date. The Gram-positive antibacterial activity in selected strains is also presented.