Phosphate prodrugs of PD154075.

In the preparation of phosphate prodrugs of PD154075, several strategies of linking a phosphate group to the indole moiety were studied. A novel linker, p-hydroxymethylbenzoyloxymethoxycarbonyl, was discovered to provide the phosphate prodrug of PD154075 (compound 9) with significantly increased aqueous solubility, sufficient stability in aqueous solution and good bio-reconversion in vivo.

An efficient stereoselective synthesis of [3S(1S,9S)]-3-[[[9-(benzoylamino) octahydro-6,10-dioxo-6H-pyridazino-(1,2-a)(1,2)-diazepin-1-yl]-carbonyl ]amino]-4-oxobutanoic acid, an interleukin converting enzyme (ICE) inhibitor.

The title compound 1 is a potent interleukin-1beta-converting enzyme (ICE) inhibitor. Recently, an efficient chiral synthesis of compound 1 has been accomplished in our labs. The overall yield of this 18-step stereoselective synthesis was 9.8%.

Bioactivation and irreversible binding of the cognition activator tacrine using human and rat liver microsomal preparations. Species difference.

Tacrine's [1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate, (THA)] metabolic fate was examined using human and rat liver microsomal preparations. Following 1-hr incubations with human microsomes, [14C]THA (0.4 microM) was extensively metabolized to 1-hydroxyTHA with trace amounts of 2-, 4-, and 7-hydroxyTHA also produced. Poor recovery of radioactivity in the postreaction incubates suggested association of THA-derived radioactivity with precipitated microsomal protein. After exhaustive extraction, 0.034, 0.145, 0.126, and 0.012 nmol eq bound/mg protein/60 min of THA-derived radioactivity was bound to human liver preparations H109, H111, H116, and H118, respectively. Preparations H109 and H118 were lower in P4501A2 content and catalytic activity as compared with preparations H111 and H116. Incubations of equimolar [14C]1-hydroxyTHA with human liver microsomes also resulted in binding to protein, although to a lesser extent than observed with THA. [14C]THA (0.4 microM) was incubated for 1 hr with rat liver microsomes (1 microM P-450) prepared from noninduced (N), phenobarbital (PB), isoniazid (I), and 3-methylcholanthrene (3-MC)-pretreated animals. In all incubations, 1-hydroxyTHA was the major biotransformation product detected. After exhaustive extraction, 0.048, 0.054, 0.049, and 0.153 nmol eq/mg protein/60 min of THA-derived radioactivity was bound to microsomal protein from N, PB, I, and 3-MC pretreated rats. Increased binding with 3-MC induced rat liver preparations suggests the involvement of the P-450 1A subfamily in THA bioactivation. Glutathione (5 mM) coincubation inhibited the irreversible binding of THA-derived radioactivity in both human and 3-MC-induced rat liver preparations, whereas human epoxide hydrase (100 micrograms/incubate) had a relative minor effect. A mechanism is proposed involving a putative quinone methide(s) intermediate in the bioactivation and irreversible binding of THA. A species difference in THA-derived irreversible binding exists between human and noninduced rat liver microsomes, suggesting that the rat is a poor model for studying the underlying mechanism(s) of THA-induced elevations in liver marker enzymes found in clinical investigations.

A study of the characteristics of acceptors of copper-T device: compared to other IUDs.

PIP: Data from 2011 women attending 16 centers in the states of Andhra Pradesh, Haryana, Uttar Pradesh, and Delhi, between February 1971-April 30, 1974, fitted with the Tcu-200 were compared with the results of the IUD study, a 4-year follow-up of IUD acceptors, and a study of IUD acceptors by the Operations Research Group (ORG). 2/3 of the Tcu-200 acceptors were below 30 years of age compared with 54% in the IUD study and 34% in the ORG study. Tcu-200 acceptors had fewer children (1.9 for Tcu, 4.2 for IUD, and 2.9 for ORG). 52% of the Tcu-200 users accepted the device within 6 months of pregnancy and had a shorter interval between pregnancies. 46% of the users of Tcu-200 accepted the IUD for spacing of children corresponding to 65 and 35%, respectively, for the other studies. For 37% of the Tcu-200 users, this was their 1st experience with a contraceptive device compared with 83.4% of IUD acceptors. 63% of Tcu-200 users were without complaints compared with 41% of IUD users. Bleeding was the primary cause of removal. During the first 6 months following insertion, 16% had the device removed and this rose to 39.1% after 2 years. The experience with the Tcu-200 is slightly better than with other IUDs.^ieng