Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.16 (HIV-1 protease)
 2,107 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of novel P1/P1'-substituted cyclic urea-based HIV-1 protease inhibitors was prepared. Three different synthetic schemes were used to assemble these compounds. The first approach uses amino acid-based starting materials and was originally used to prepare DMP 323. The other two approaches use L-tartaric acid or L-mannitol as the starting material. The required four contiguous R,S,S,R centers of the cyclic urea scaffold are introduced using substrate control methodology. Each approach has specific advantages based on the desired P1/P1' substituent. Designing analogs based on the enzyme's natural substrates provided compounds with reduced activity. Attempts at exploiting hydrogen bond sites in the S1/S1' pocket, suggested by molecular modeling studies, were not fruitful. Several analogs had better binding affinity compared to our initial leads. Modulating the compound's physical properties led to a 10-fold improvement in translation resulting in better overall antiviral activity.
 ...
PMID:Preparation and structure-activity relationship of novel P1/P1'-substituted cyclic urea-based human immunodeficiency virus type-1 protease inhibitors. 866 59

DMP 323, a potent HIV-1 protease inhibitor, has been synthesized by an efficient stereoselective process, amenable to large scale preparations. The core C(2) symmetric diol was synthesized by a stereoselective pinacol coupling of CBZ protected D-phenylalanine. Judicious selection of protecting groups allowed cyclic urea formation under mild conditions, enhanced the ease of bis-alkylation, and led to intermediates which were easily purified without chromatography. Additionally, a one-pot, high yield process was developed to prepare the alkylating agent, 4-[(triphenylmethoxy)methyl]benzyl chloride from 1,4-benzenedimethanol.
 ...
PMID:Stereoselective Synthesis of HIV-1 Protease Inhibitor, DMP 323. 1166 58

Cyclic ureas form a perspective class of non-peptidic HIV-1 protease inhibitors with major bioavailability problems. Low absorption rates of DMP 323 as one of the first representatives led to investigations whether transport efflux pump P-glycoprotein (P-gp) within the intestine may be partly responsible for the low absorption rates. DMP 323 proved to be a P-gp substrate in competition studies with P-gp inhibitor ritonavir and H17 as a representative of another class of non-peptidic HIV-1 protease inhibitors. Intestinal DMP 323 absorption was mainly increased under co-application of both ritonavir and H17. DMP 323 used as a membrane efflux pump inhibitor itself showed little affinities to P-gp compared to H17 as strong P-gp inhibitor. So P-gp proved to play a decisive role in the low intestinal absorption of the cyclic urea representative DMP 323.
 ...
PMID:P-glycoprotein effects of cyclic urea HIV protease inhibitor DMP 323 in competitional absorption studies. 1704 92